Friend or Foe: Regulation, Downstream Effectors of RRAD in Cancer
Abstract
:1. Introduction
2. Regulation of RRAD
2.1. DNA Methylation
2.2. Histone Demethylation
2.3. Transcription Factors Alteration
3. Diverse Downstream Effectors of RRAD
3.1. RRAD as Tumor Suppressor Gene
3.1.1. Cell Signaling
3.1.2. Cancer Cell Proliferation
3.1.3. Cancer Cell Migration
3.1.4. Energy Utilization
3.2. RRAD as Oncogene
3.2.1. Cell Signaling
3.2.2. Cancer Cell Proliferation and Migration
3.2.3. Energy Utilization
3.3. RRAD in Senescence Contributes to Tumor Progression
3.4. RRAD as a Potential Drug Target
4. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviation
AH | Anthelmintics |
PKA | cAMP-dependent protein kinase |
CRC | Colorectal cancer |
CID | CHD4-interacting domain |
PARP | cleaved poly (ADP-ribose) polymerase/caspase-3 |
DNMTs | DNA methyltransferases |
EGR | Early growth response family |
EGFR | Epidermal growth factor receptor |
GC | Gastric cancer |
GLUT | glucose transporter |
GCIP | Grap2 and cyclin D interacting protein |
GAP | GTPase-activating protein |
GEF | Guanine nucleotide exchange factor |
HK-II | Hexokinase-II |
HDAC | Histone deacetylases |
HRE | Hypoxia response element |
HIF-1α | Hypoxia-inducible factor-1α |
MI | Microtubule inhibitors |
NAB1/2 | NGFI-A binding protein |
NSCLC | Non-small-cell lung cancer |
NES | Nuclear export signals |
NLS | Nuclear localization signals |
NuRD | Nucleosome remodeling and deacetylase complex |
PM | Plasma membrane |
PDGF | Platelet-Derived Growth Factor |
PKC | Protein kinase C |
RRTF | Ras-responsive transcription factor |
ROS | Reactive oxygen species |
Rb | Retinoblastoma protein |
ROCK | Rho-associated protein kinase |
SASP | Senescence-associated secretory phenotype |
TI | Topoisomerase inhibitors |
References
- Reynet, C.; Kahn, C.R. Rad: A member of the Ras family overexpressed in muscle of type II diabetic humans. Science 1993, 262, 1441–1444. [Google Scholar] [CrossRef]
- Ward, Y.; Yap, S.F.; Ravichandran, V.; Matsumura, F.; Ito, M.; Spinelli, B.; Kelly, K. The GTP binding proteins Gem and Rad are negative regulators of the Rho-Rho kinase pathway. J. Cell Biol. 2002, 157, 291–302. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yanuar, A.; Sakurai, S.; Kitano, K.; Hakoshima, T. Crystal structure of human Rad GTPase of the RGK-family. Genes Cells 2006, 11, 961–968. [Google Scholar] [CrossRef] [PubMed]
- Correll, R.N.; Pang, C.; Niedowicz, D.M.; Finlin, B.S.; Andres, D.A. The RGK family of GTP-binding proteins: Regulators of voltage-dependent calcium channels and cytoskeleton remodeling. Cell Signal. 2008, 20, 292–300. [Google Scholar] [CrossRef] [Green Version]
- Kelly, K. The RGK family: A regulatory tail of small GTP-binding proteins. Trends. Cell Biol. 2005, 15, 640–643. [Google Scholar] [CrossRef]
- Downward, J. Regulatory mechanisms for ras proteins. Bioessays 1992, 14, 177–184. [Google Scholar] [CrossRef]
- Lu, Q.; Wang, P.S.; Yang, L. Golgi-associated Rab GTPases implicated in autophagy. Cell Biosci. 2021, 11, 35. [Google Scholar] [CrossRef]
- Ridley, A.J.; Hall, A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 1992, 70, 389–399. [Google Scholar] [CrossRef]
- Malumbres, M.; Barbacid, M. RAS oncogenes: The first 30 years. Nat. Rev. Cancer 2003, 3, 459–465. [Google Scholar] [CrossRef] [PubMed]
- Bernal Astrain, G.; Nikolova, M.; Smith, M.J. Functional diversity in the RAS subfamily of small GTPases. Biochem Soc. Trans. 2022, 50, 921–933. [Google Scholar] [CrossRef]
- Moyers, J.S.; Bilan, P.J.; Reynet, C.; Kahn, C.R. Overexpression of Rad inhibits glucose uptake in cultured muscle and fat cells. J. Biol. Chem. 1996, 271, 23111–23116. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Moyers, J.S.; Bilan, P.J.; Zhu, J.; Kahn, C.R. Rad and Rad-related GTPases interact with calmodulin and calmodulin-dependent protein kinase II. J. Biol. Chem. 1997, 272, 11832–11839. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yan, Y.; Xu, H.; Zhang, L.; Zhou, X.; Qian, X.; Zhou, J.; Huang, Y.; Ge, W.; Wang, W. RRAD suppresses the Warburg effect by downregulating ACTG1 in hepatocellular carcinoma. Onco. Targets Ther. 2019, 12, 1691–1703. [Google Scholar] [CrossRef] [Green Version]
- Barnoud, T.; Parris, J.L.D.; Murphy, M.E. Tumor cells containing the African-Centric S47 variant of TP53 show increased Warburg metabolism. Oncotarget 2019, 10, 1217–1223. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yan, Y.; Xie, M.; Zhang, L.; Zhou, X.; Xie, H.; Zhou, L.; Zheng, S.; Wang, W. Ras-related associated with diabetes gene acts as a suppressor and inhibits Warburg effect in hepatocellular carcinoma. Onco. Targets Ther. 2016, 9, 3925–3937. [Google Scholar] [CrossRef] [Green Version]
- Shang, R.; Wang, J.; Sun, W.; Dai, B.; Ruan, B.; Zhang, Z.; Yang, X.; Gao, Y.; Qu, S.; Lv, X.; et al. RRAD inhibits aerobic glycolysis, invasion, and migration and is associated with poor prognosis in hepatocellular carcinoma. Tumour Biol. 2016, 37, 5097–5105. [Google Scholar] [CrossRef]
- Zhao, W.; Mo, Y.; Wang, S.; Midorikawa, K.; Ma, N.; Hiraku, Y.; Oikawa, S.; Huang, G.; Zhang, Z.; Murata, M.; et al. Quantitation of DNA methylation in Epstein-Barr virus-associated nasopharyngeal carcinoma by bisulfite amplicon sequencing. BMC Cancer 2017, 17, 489. [Google Scholar] [CrossRef] [Green Version]
- Mo, Y.; Midorikawa, K.; Zhang, Z.; Zhou, X.; Ma, N.; Huang, G.; Hiraku, Y.; Oikawa, S.; Murata, M. Promoter hypermethylation of Ras-related GTPase gene RRAD inactivates a tumor suppressor function in nasopharyngeal carcinoma. Cancer Lett. 2012, 323, 147–154. [Google Scholar] [CrossRef]
- Wei, C.C.; Nie, F.Q.; Jiang, L.L.; Chen, Q.N.; Chen, Z.Y.; Chen, X.; Pan, X.; Liu, Z.L.; Lu, B.B.; Wang, Z.X. The pseudogene DUXAP10 promotes an aggressive phenotype through binding with LSD1 and repressing LATS2 and RRAD in non small cell lung cancer. Oncotarget 2017, 8, 5233–5246. [Google Scholar] [CrossRef] [Green Version]
- Gu, N.J.; Wu, M.Z.; He, L.; Wang, X.B.; Wang, S.; Qiu, X.S.; Wang, E.H.; Wu, G.P. HPV 16 E6/E7 up-regulate the expression of both HIF-1alpha and GLUT1 by inhibition of RRAD and activation of NF-kappaB in lung cancer cells. J. Cancer 2019, 10, 6903–6909. [Google Scholar] [CrossRef]
- Hsiao, B.Y.; Chang, T.K.; Wu, I.T.; Chen, M.Y. Rad GTPase inhibits the NFkappaB pathway through interacting with RelA/p65 to impede its DNA binding and target gene transactivation. Cell Signal. 2014, 26, 1437–1444. [Google Scholar] [CrossRef] [PubMed]
- Zhang, C.; Liu, J.; Wu, R.; Liang, Y.; Lin, M.; Liu, J.; Chan, C.S.; Hu, W.; Feng, Z. Tumor suppressor p53 negatively regulates glycolysis stimulated by hypoxia through its target RRAD. Oncotarget 2014, 5, 5535–5546. [Google Scholar] [CrossRef] [Green Version]
- Song, S.; Walter, V.; Karaca, M.; Li, Y.; Bartlett, C.S.; Smiraglia, D.J.; Serber, D.; Sproul, C.D.; Plass, C.; Zhang, J.; et al. Gene silencing associated with SWI/SNF complex loss during NSCLC development. Mol. Cancer. Res. 2014, 12, 560–570. [Google Scholar] [CrossRef] [Green Version]
- Hsiao, B.Y.; Chen, C.C.; Hsieh, P.C.; Chang, T.K.; Yeh, Y.C.; Wu, Y.C.; Hsu, H.S.; Wang, F.F.; Chou, T.Y. Rad is a p53 direct transcriptional target that inhibits cell migration and is frequently silenced in lung carcinoma cells. J. Mol. Med. 2011, 89, 481–492. [Google Scholar] [CrossRef]
- Phelps, R.M.; Johnson, B.E.; Ihde, D.C.; Gazdar, A.F.; Carbone, D.P.; McClintock, P.R.; Linnoila, R.I.; Matthews, M.J.; Bunn, P.A., Jr.; Carney, D.; et al. NCI-Navy Medical Oncology Branch cell line data base. J. Cell Biochem. Suppl. 1996, 24, 32–91. [Google Scholar] [CrossRef]
- Suzuki, M.; Shigematsu, H.; Shames, D.S.; Sunaga, N.; Takahashi, T.; Shivapurkar, N.; Iizasa, T.; Minna, J.D.; Fujisawa, T.; Gazdar, A.F. Methylation and gene silencing of the Ras-related GTPase gene in lung and breast cancers. Ann. Surg. Oncol. 2007, 14, 1397–1404. [Google Scholar] [CrossRef]
- Tseng, Y.H.; Vicent, D.; Zhu, J.; Niu, Y.; Adeyinka, A.; Moyers, J.S.; Watson, P.H.; Kahn, C.R. Regulation of growth and tumorigenicity of breast cancer cells by the low molecular weight GTPase Rad and nm23. Cancer Res. 2001, 61, 2071–2079. [Google Scholar]
- Sova, P.; Feng, Q.; Geiss, G.; Wood, T.; Strauss, R.; Rudolf, V.; Lieber, A.; Kiviat, N. Discovery of novel methylation biomarkers in cervical carcinoma by global demethylation and microarray analysis. Cancer Epidemiol. Biomarkers Prev. 2006, 15, 114–123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ma, J.; Hou, X.; Li, M.; Ren, H.; Fang, S.; Wang, X.; He, C. Genome-wide methylation profiling reveals new biomarkers for prognosis prediction of glioblastoma. J. Cancer Res. Ther. 2015, 11 (Suppl. S2), C212–C215. [Google Scholar]
- Jin, Z.; Feng, X.; Jian, Q.; Cheng, Y.; Gao, Y.; Zhang, X.; Wang, L.; Zhang, Y.; Huang, W.; Fan, X.; et al. Aberrant methylation of the Ras-related associated with diabetes gene in human primary esophageal cancer. Anticancer Res. 2013, 33, 5199–5203. [Google Scholar] [PubMed]
- Wang, Y.; Li, G.; Mao, F.; Li, X.; Liu, Q.; Chen, L.; Lv, L.; Wang, X.; Wu, J.; Dai, W.; et al. Ras-induced epigenetic inactivation of the RRAD (Ras-related associated with diabetes) gene promotes glucose uptake in a human ovarian cancer model. J. Biol. Chem. 2014, 289, 14225–14238. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Guo, J.; Zhu, Y.; Yu, L.; Li, Y.; Guo, J.; Cai, J.; Liu, L.; Wang, Z. Aspirin inhibits tumor progression and enhances cisplatin sensitivity in epithelial ovarian cancer. PeerJ 2021, 9, e11591. [Google Scholar] [CrossRef] [PubMed]
- Suzuki, M.; Toyooka, S.; Shivapurkar, N.; Shigematsu, H.; Miyajima, K.; Takahashi, T.; Stastny, V.; Zern, A.L.; Fujisawa, T.; Pass, H.I.; et al. Aberrant methylation profile of human malignant mesotheliomas and its relationship to SV40 infection. Oncogene 2005, 24, 1302–1308. [Google Scholar] [CrossRef] [Green Version]
- Yeom, S.Y.; Nam, D.H.; Park, C. RRAD promotes EGFR-mediated STAT3 activation and induces temozolomide resistance of malignant glioblastoma. Mol. Cancer Ther. 2014, 13, 3049–3061. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- ·Lee, S.J.; Yeom, S.Y.; Lee, J.Y.; Park, C. Application of the antitussive agents oxelaidin and butamirate as anti-glioma agents. Sci. Rep. 2021, 11, 10145. [Google Scholar] [CrossRef]
- Lin, Z.Y.; Chuang, W.L. Genes responsible for the characteristics of primary cultured invasive phenotype hepatocellular carcinoma cells. Biomed. Pharmacother. 2012, 66, 454–458. [Google Scholar] [CrossRef]
- Wei, Z.; Guo, H.; Qin, J.; Lu, S.; Liu, Q.; Zhang, X.; Zou, Y.; Gong, Y.; Shao, C. Pan-senescence transcriptome analysis identified RRAD as a marker and negative regulator of cellular senescence. Free Radic. Biol. Med. 2019, 130, 267–277. [Google Scholar] [CrossRef]
- Yeom, S.Y.; Lee, S.J.; Kim, W.S.; Park, C. Rad knockdown induces mitochondrial apoptosis in bortezomib resistant leukemia and lymphoma cells. Leuk. Res. 2012, 36, 1172–1178. [Google Scholar] [CrossRef]
- Kim, H.K.; Lee, I.; Kim, S.T.; Lee, J.; Kim, K.M.; Park, J.O.; Kang, W.K. RRAD expression in gastric and colorectal cancer with peritoneal carcinomatosis. Sci. Rep. 2019, 9, 19439. [Google Scholar] [CrossRef] [Green Version]
- Svaren, J.; Ehrig, T.; Abdulkadir, S.A.; Ehrengruber, M.U.; Watson, M.A.; Milbrandt, J. EGR1 target genes in prostate carcinoma cells identified by microarray analysis. J. Biol. Chem. 2000, 275, 38524–38531. [Google Scholar] [CrossRef] [Green Version]
- Zhu, J.; Tseng, Y.H.; Kantor, J.D.; Rhodes, C.J.; Zetter, B.R.; Moyers, J.S.; Kahn, C.R. Interaction of the Ras-related protein associated with diabetes rad and the putative tumor metastasis suppressor NM23 provides a novel mechanism of GTPase regulation. Proc. Natl. Acad. Sci. USA 1999, 96, 14911–14918. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, J.; Zhang, C.; Wu, R.; Lin, M.; Liang, Y.; Liu, J.; Wang, X.; Yang, B.; Feng, Z. RRAD inhibits the Warburg effect through negative regulation of the NF-kappaB signaling. Oncotarget 2015, 6, 14982–14992. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bos, J.L. Ras oncogenes in human cancer: A review. Cancer Res. 1989, 49, 4682–4689. [Google Scholar] [PubMed]
- Kalamanathan, S.; Bates, V.; Lord, R.; Green, J.A. The mutational profile of sporadic epithelial ovarian carcinoma. Anticancer Res. 2011, 31, 2661–2668. [Google Scholar] [PubMed]
- Wittinghofer, A. Signal transduction via Ras. Biol. Chem. 1998, 379, 933–937. [Google Scholar]
- Kilic Eren, M.; Tabor, V. The role of hypoxia inducible factor-1 alpha in bypassing oncogene-induced senescence. PLoS ONE 2014, 9, e101064. [Google Scholar] [CrossRef] [Green Version]
- Sebastian, T.; Malik, R.; Thomas, S.; Sage, J.; Johnson, P.F. C/EBPbeta cooperates with RB:E2F to implement Ras(V12)-induced cellular senescence. Embo J. 2005, 24, 3301–3312. [Google Scholar] [CrossRef] [Green Version]
- Chen, Y.; Jie, W.; Yan, W.; Zhou, K.; Xiao, Y. Lysine-specific histone demethylase 1 (LSD1): A potential molecular target for tumor therapy. Crit. Rev. Eukaryot. Gene Expr. 2012, 22, 53–59. [Google Scholar] [CrossRef]
- Wilson, B.G.; Roberts, C.W. SWI/SNF nucleosome remodellers and cancer. Nat. Rev. Cancer 2011, 11, 481–492. [Google Scholar] [CrossRef]
- Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012, 489, 519–525. [Google Scholar] [CrossRef] [Green Version]
- Imielinski, M.; Berger, A.H.; Hammerman, P.S.; Hernandez, B.; Pugh, T.J.; Hodis, E.; Cho, J.; Suh, J.; Capelletti, M.; Sivachenko, A.; et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 2012, 150, 1107–1120. [Google Scholar] [CrossRef] [Green Version]
- Kothandapani, A.; Gopalakrishnan, K.; Kahali, B.; Reisman, D.; Patrick, S.M. Downregulation of SWI/SNF chromatin remodeling factor subunits modulates cisplatin cytotoxicity. Exp. Cell Res. 2012, 318, 1973–1986. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, D.; Kim, J.W.; Seo, T.; Hwang, S.G.; Choi, E.J.; Choe, J. SWI/SNF complex interacts with tumor suppressor p53 and is necessary for the activation of p53-mediated transcription. J. Biol. Chem. 2002, 277, 22330–22337. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cheng, S.W.; Davies, K.P.; Yung, E.; Beltran, R.J.; Yu, J.; Kalpana, G.V. c-MYC interacts with INI1/hSNF5 and requires the SWI/SNF complex for transactivation function. Nat. Genet. 1999, 22, 102–105. [Google Scholar] [CrossRef] [PubMed]
- Zhang, J.; Ohta, T.; Maruyama, A.; Hosoya, T.; Nishikawa, K.; Maher, J.M.; Shibahara, S.; Itoh, K.; Yamamoto, M. BRG1 interacts with Nrf2 to selectively mediate HO-1 induction in response to oxidative stress. Mol. Cell Biol. 2006, 26, 7942–7952. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, Z.; Zhang, X.; Liu, S.; Zeng, S.; Yu, L.; Yang, G.; Guo, J.; Xu, Y. BRG1 regulates NOX gene transcription in endothelial cells and contributes to cardiac ischemia-reperfusion injury. Biochim. Biophys. Acta Mol. Basis Dis. 2018, 1864, 3477–3486. [Google Scholar] [CrossRef]
- Tolstorukov, M.Y.; Sansam, C.G.; Lu, P.; Koellhoffer, E.C.; Helming, K.C.; Alver, B.H.; Tillman, E.J.; Evans, J.A.; Wilson, B.G.; Park, P.J.; et al. Swi/Snf chromatin remodeling/tumor suppressor complex establishes nucleosome occupancy at target promoters. Proc. Natl. Acad. Sci. USA 2013, 110, 10165–10170. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hassan, A.H.; Prochasson, P.; Neely, K.E.; Galasinski, S.C.; Chandy, M.; Carrozza, M.J.; Workman, J.L. Function and selectivity of bromodomains in anchoring chromatin-modifying complexes to promoter nucleosomes. Cell 2002, 111, 369–379. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Trotter, K.W.; Archer, T.K. The BRG1 transcriptional coregulator. Nucl. Recept Signal. 2008, 6, e004. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, I.; Yeom, S.Y.; Lee, S.J.; Kang, W.K.; Park, C. A novel senescence-evasion mechanism involving Grap2 and Cyclin D interacting protein inactivation by Ras associated with diabetes in cancer cells under doxorubicin treatment. Cancer Res. 2010, 70, 4357–4365. [Google Scholar] [CrossRef] [Green Version]
- Jennis, M.; Kung, C.P.; Basu, S.; Budina-Kolomets, A.; Leu, J.I.; Khaku, S.; Scott, J.P.; Cai, K.Q.; Campbell, M.R.; Porter, D.K.; et al. An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model. Genes Dev. 2016, 30, 918–930. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Murphy, M.E.; Liu, S.; Yao, S.; Huo, D.; Liu, Q.; Dolfi, S.C.; Hirshfield, K.M.; Hong, C.C.; Hu, Q.; Olshan, A.F.; et al. A functionally significant SNP in TP53 and breast cancer risk in African-American women. NPJ Breast Cancer 2017, 3, 5. [Google Scholar] [CrossRef] [PubMed]
- Chlon, T.; Hoskins, E.; Mayhew, C.; Wikenheiser-Brokamp, K.; Davies, S.; Mehta, P.; Myers, K.; Wells, J.; Wells, S.J.J.o.v. High-risk human papillomavirus E6 protein promotes reprogramming of Fanconi anemia patient cells through repression of p53 but does not allow for sustained growth of induced pluripotent stem cells. J. Virol. 2014, 88, 11315–11326. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Todorovic, B.; Hung, K.; Massimi, P.; Avvakumov, N.; Dick, F.; Shaw, G.; Banks, L.; Mymryk, J.J.J.o.v. Conserved region 3 of human papillomavirus 16 E7 contributes to deregulation of the retinoblastoma tumor suppressor. J. Virol. 2012, 86, 13313–13323. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dimitrakopoulos, F.D.; Antonacopoulou, A.G.; Kottorou, A.E.; Panagopoulos, N.; Kalofonou, F.; Sampsonas, F.; Scopa, C.; Kalofonou, M.; Koutras, A.; Makatsoris, T.; et al. Expression Of Intracellular Components of the NF-κB Alternative Pathway (NF-κB2, RelB, NIK and Bcl3) is Associated With Clinical Outcome of NSCLC Patients. Sci. Rep. 2019, 9, 14299. [Google Scholar] [CrossRef] [Green Version]
- Cogswell, P.C.; Guttridge, D.C.; Funkhouser, W.K.; Baldwin, A.S., Jr. Selective activation of NF-kappa B subunits in human breast cancer: Potential roles for NF-kappa B2/p52 and for Bcl-3. Oncogene 2000, 19, 1123–1131. [Google Scholar] [CrossRef] [Green Version]
- Lovas, A.; Weidemann, A.; Albrecht, D.; Wiechert, L.; Weih, D.; Weih, F. p100 Deficiency is insufficient for full activation of the alternative NF-kappaB pathway: TNF cooperates with p52-RelB in target gene transcription. PLoS ONE 2012, 7, e42741. [Google Scholar] [CrossRef]
- Szoltysek, K.; Janus, P.; Zajac, G.; Stokowy, T.; Walaszczyk, A.; Widlak, W.; Wojtas, B.; Gielniewski, B.; Cockell, S.; Perkins, N.D.; et al. RRAD, IL4I1, CDKN1A, and SERPINE1 genes are potentially co-regulated by NF-kappaB and p53 transcription factors in cells exposed to high doses of ionizing radiation. BMC Genomics 2018, 19, 813. [Google Scholar] [CrossRef]
- Russo, M.W.; Sevetson, B.R.; Milbrandt, J. Identification of NAB1, a repressor of NGFI-A- and Krox20-mediated transcription. Proc. Natl. Acad. Sci. USA 1995, 92, 6873–6877. [Google Scholar] [CrossRef] [Green Version]
- Svaren, J.; Sevetson, B.R.; Apel, E.D.; Zimonjic, D.B.; Popescu, N.C.; Milbrandt, J. NAB2, a corepressor of NGFI-A (Egr-1) and Krox20, is induced by proliferative and differentiative stimuli. Mol. Cell Biol. 1996, 16, 3545–3553. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sevetson, B.R.; Svaren, J.; Milbrandt, J. A novel activation function for NAB proteins in EGR-dependent transcription of the luteinizing hormone beta gene. J. Biol. Chem. 2000, 275, 9749–9757. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zang, C.S.; Huang, H.T.; Qiu, J.; Sun, J.; Ge, R.F.; Jiang, L.W. MiR-224-5p targets EGR2 to promote the development of papillary thyroid carcinoma. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 4890–4900. [Google Scholar] [PubMed]
- Abdulkadir, S.A.; Carbone, J.M.; Naughton, C.K.; Humphrey, P.A.; Catalona, W.J.; Milbrandt, J. Frequent and early loss of the EGR1 corepressor NAB2 in human prostate carcinoma. Hum. Pathol. 2001, 32, 935–939. [Google Scholar] [CrossRef] [PubMed]
- Luo, Y.; Zhang, M.; Zhang, J.; Zhang, J.; Chen, C.; Chen, Y.E.; Xiong, J.W.; Zhu, X. Platelet-derived growth factor induces Rad expression through Egr-1 in vascular smooth muscle cells. PLoS ONE 2011, 6, e19408. [Google Scholar] [CrossRef] [Green Version]
- Gialeli, C.; Nikitovic, D.; Kletsas, D.; Theocharis, A.D.; Tzanakakis, G.N.; Karamanos, N.K. PDGF/PDGFR signaling and targeting in cancer growth and progression: Focus on tumor microenvironment and cancer-associated fibroblasts. Curr. Pharm. Des. 2014, 20, 2843–2848. [Google Scholar] [CrossRef] [PubMed]
- Primac, I.; Maquoi, E.; Blacher, S.; Heljasvaara, R.; Van Deun, J.; Smeland, H.Y.; Canale, A.; Louis, T.; Stuhr, L.; Sounni, N.E.; et al. Stromal integrin α11 regulates PDGFR-β signaling and promotes breast cancer progression. J. Clin. Invest. 2019, 129, 4609–4628. [Google Scholar] [CrossRef] [Green Version]
- Srinivasan, R.; Mager, G.M.; Ward, R.M.; Mayer, J.; Svaren, J. NAB2 represses transcription by interacting with the CHD4 subunit of the nucleosome remodeling and deacetylase (NuRD) complex. J. Biol. Chem. 2006, 281, 15129–15137. [Google Scholar] [CrossRef] [Green Version]
- Hayden, M.S.; Ghosh, S. NF-κB, the first quarter-century: Remarkable progress and outstanding questions. Genes Dev. 2012, 26, 203–234. [Google Scholar] [CrossRef] [Green Version]
- Ghosh, S.; Karin, M. Missing pieces in the NF-kappaB puzzle. Cell 2002, 109 (Suppl. S1), S81–S96. [Google Scholar] [CrossRef] [Green Version]
- Aguilera, C.; Fernandez-Majada, V.; Ingles-Esteve, J.; Rodilla, V.; Bigas, A.; Espinosa, L. Efficient nuclear export of p65-IkappaBalpha complexes requires 14-3-3 proteins. J. Cell Sci. 2016, 129, 2472. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Qi, X.; Xu, W.; Xie, J.; Wang, Y.; Han, S.; Wei, Z.; Ni, Y.; Dong, Y.; Han, W. Metformin sensitizes the response of oral squamous cell carcinoma to cisplatin treatment through inhibition of NF-κB/HIF-1α signal axis. Sci. Rep. 2016, 6, 35788. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Christian, F.; Smith, E.L.; Carmody, R.J. The Regulation of NF-κB Subunits by Phosphorylation. Cells 2016, 5, 12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, Y.; Sui, H.; Jiang, C.; Li, S.; Han, Y.; Huang, P.; Du, X.; Du, J.; Bai, Y. Dihydroartemisinin Increases the Sensitivity of Photodynamic Therapy Via NF-κB/HIF-1α/VEGF Pathway in Esophageal Cancer Cell in vitro and in vivo. Cell Physiol Biochem 2018, 48, 2035–2045. [Google Scholar] [CrossRef]
- Zhang, T.; Guo, S.; Zhu, X.; Qiu, J.; Deng, G.; Qiu, C. Alpinetin inhibits breast cancer growth by ROS/NF-κB/HIF-1α axis. J. Cell Mol. Med. 2020, 24, 8430–8440. [Google Scholar] [CrossRef] [PubMed]
- Song, Y.; Zou, X.; Zhang, D.; Liu, S.; Duan, Z.; Liu, L. Self-enforcing HMGB1/NF-κB/HIF-1α Feedback Loop Promotes Cisplatin Resistance in Hepatocellular Carcinoma Cells. J. Cancer 2020, 11, 3893–3902. [Google Scholar] [CrossRef] [PubMed]
- Sato, H.; Kida, Y.; Mai, M.; Endo, Y.; Sasaki, T.; Tanaka, J.; Seiki, M. Expression of genes encoding type IV collagen-degrading metalloproteinases and tissue inhibitors of metalloproteinases in various human tumor cells. Oncogene 1992, 7, 77–83. [Google Scholar] [PubMed]
- Simanshu, D.K.; Nissley, D.V.; McCormick, F. RAS Proteins and Their Regulators in Human Disease. Cell 2017, 170, 17–33. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lyshchik, A.; Higashi, T.; Hara, T.; Nakamoto, Y.; Fujimoto, K.; Doi, R.; Imamura, M.; Saga, T.; Togashi, K.J.C.i. Expression of glucose transporter-1, hexokinase-II, proliferating cell nuclear antigen and survival of patients with pancreatic cancer. Cancer Investig. 2007, 25, 154–162. [Google Scholar] [CrossRef]
- Mamede, M.; Higashi, T.; Kitaichi, M.; Ishizu, K.; Ishimori, T.; Nakamoto, Y.; Yanagihara, K.; Li, M.; Tanaka, F.; Wada, H.; et al. [18F]FDG uptake and PCNA, Glut-1, and Hexokinase-II expressions in cancers and inflammatory lesions of the lung. Neoplasia 2005, 7, 369–379. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Maxwell, P.; Wiesener, M.; Chang, G.; Clifford, S.; Vaux, E.; Cockman, M.; Wykoff, C.; Pugh, C.; Maher, E.; Ratcliffe, P.J.N. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999, 399, 271–275. [Google Scholar] [CrossRef] [PubMed]
- Jaakkola, P.; Mole, D.R.; Tian, Y.M.; Wilson, M.I.; Gielbert, J.; Gaskell, S.J.; von Kriegsheim, A.; Hebestreit, H.F.; Mukherji, M.; Schofield, C.J.; et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001, 292, 468–472. [Google Scholar] [CrossRef] [PubMed]
- Tsai, L.H.; Harlow, E.; Meyerson, M. Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase. Nature 1991, 353, 174–177. [Google Scholar] [CrossRef]
- Kimura, K.; Hirano, M.; Kobayashi, R.; Hirano, T. Phosphorylation and activation of 13S condensin by Cdc2 in vitro. Science 1998, 282, 487–490. [Google Scholar] [CrossRef]
- Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol. 2007, 35, 495–516. [Google Scholar] [CrossRef]
- Gu, W.; Li, C.; Yin, W.; Guo, Z.; Hou, X.; Zhang, D. Shen-fu injection reduces postresuscitation myocardial dysfunction in a porcine model of cardiac arrest by modulating apoptosis. Shock 2012, 38, 301–306. [Google Scholar] [CrossRef]
- Sumi, T.; Matsumoto, K.; Takai, Y.; Nakamura, T. Cofilin phosphorylation and actin cytoskeletal dynamics regulated by rho- and Cdc42-activated LIM-kinase 2. J. Cell Biol. 1999, 147, 1519–1532. [Google Scholar] [CrossRef] [Green Version]
- Mahalakshmi, R.N.; Ng, M.Y.; Guo, K.; Qi, Z.; Hunziker, W.; Béguin, P. Nuclear localization of endogenous RGK proteins and modulation of cell shape remodeling by regulated nuclear transport. Traffic 2007, 8, 1164–1178. [Google Scholar] [CrossRef] [PubMed]
- Soosairajah, J.; Maiti, S.; Wiggan, O.; Sarmiere, P.; Moussi, N.; Sarcevic, B.; Sampath, R.; Bamburg, J.R.; Bernard, O. Interplay between components of a novel LIM kinase-slingshot phosphatase complex regulates cofilin. Embo J. 2005, 24, 473–486. [Google Scholar] [CrossRef] [PubMed]
- Liberti, M.V.; Locasale, J.W. The Warburg Effect: How Does it Benefit Cancer Cells? Trends. Biochem. Sci. 2016, 41, 211–218. [Google Scholar] [CrossRef] [Green Version]
- Vander Heiden, M.G.; Cantley, L.C.; Thompson, C.B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 2009, 324, 1029–1033. [Google Scholar] [CrossRef] [Green Version]
- Hirschhaeuser, F.; Sattler, U.G.; Mueller-Klieser, W. Lactate: A metabolic key player in cancer. Cancer Res. 2011, 71, 6921–6925. [Google Scholar] [CrossRef] [Green Version]
- Moyers, J.S.; Zhu, J.; Kahn, C.R. Effects of phosphorylation on function of the Rad GTPase. Biochem. J. 1998, 333 Pt 3, 609–614. [Google Scholar] [CrossRef] [Green Version]
- Zhu, J.; Reynet, C.; Caldwell, J.S.; Kahn, C.R. Characterization of Rad, a new member of Ras/GTPase superfamily, and its regulation by a unique GTPase-activating protein (GAP)-like activity. J. Biol. Chem. 1995, 270, 4805–4812. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ghezzi, C.; Wright, E.M. Regulation of the human Na+-dependent glucose cotransporter hSGLT2. Am. J. Physiol. Cell Physiol. 2012, 303, C348–C354. [Google Scholar] [CrossRef] [Green Version]
- Ojuka, E.O.; Goyaram, V.; Smith, J.A. The role of CaMKII in regulating GLUT4 expression in skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 2012, 303, E322–E331. [Google Scholar] [CrossRef] [PubMed]
- Ozcan, L.; Wong, C.C.; Li, G.; Xu, T.; Pajvani, U.; Park, S.K.; Wronska, A.; Chen, B.X.; Marks, A.R.; Fukamizu, A.; et al. Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity. Cell Metab. 2012, 15, 739–751. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bogan, J.S. Regulation of glucose transporter translocation in health and diabetes. Annu. Rev. Biochem. 2012, 81, 507–532. [Google Scholar] [CrossRef] [PubMed]
- Lymbouridou, R.; Soufla, G.; Chatzinikola, A.M.; Vakis, A.; Spandidos, D.A. Down-regulation of K-ras and H-ras in human brain gliomas. Eur. J. Cancer 2009, 45, 1294–1303. [Google Scholar] [CrossRef]
- Lo, H.W.; Cao, X.; Zhu, H.; Ali-Osman, F. Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliomas and targeting STAT3 sensitizes them to Iressa and alkylators. Clin. Cancer Res. 2008, 14, 6042–6054. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lo, H.W.; Hsu, S.C.; Xia, W.; Cao, X.; Shih, J.Y.; Wei, Y.; Abbruzzese, J.L.; Hortobagyi, G.N.; Hung, M.C. Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res. 2007, 67, 9066–9076. [Google Scholar] [CrossRef] [Green Version]
- Ahsan, A.; Ramanand, S.G.; Whitehead, C.; Hiniker, S.M.; Rehemtulla, A.; Pratt, W.B.; Jolly, S.; Gouveia, C.; Truong, K.; Van Waes, C.; et al. Wild-type EGFR is stabilized by direct interaction with HSP90 in cancer cells and tumors. Neoplasia 2012, 14, 670–677. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, S.C.; Hung, M.C. Nuclear translocation of the epidermal growth factor receptor family membrane tyrosine kinase receptors. Clin. Cancer Res. 2009, 15, 6484–6489. [Google Scholar] [CrossRef] [Green Version]
- Sato, K.; Nagao, T.; Iwasaki, T.; Nishihira, Y.; Fukami, Y. Src-dependent phosphorylation of the EGF receptor Tyr-845 mediates Stat-p21waf1 pathway in A431 cells. Genes Cells 2003, 8, 995–1003. [Google Scholar] [CrossRef] [PubMed]
- Bild, A.H.; Turkson, J.; Jove, R. Cytoplasmic transport of Stat3 by receptor-mediated endocytosis. Embo J. 2002, 21, 3255–3263. [Google Scholar] [CrossRef] [Green Version]
- Jin, W. Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial-Mesenchymal Transition. Cells 2020, 9, 217. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fong, H.; Hohenstein, K.A.; Donovan, P.J. Regulation of self-renewal and pluripotency by Sox2 in human embryonic stem cells. Stem Cells 2008, 26, 1931–1938. [Google Scholar] [CrossRef] [PubMed]
- Chung, A.S.; Lee, J.; Ferrara, N. Targeting the tumour vasculature: Insights from physiological angiogenesis. Nat. Rev. Cancer 2010, 10, 505–514. [Google Scholar] [CrossRef]
- Rigamonti, N.; Kadioglu, E.; Keklikoglou, I.; Wyser Rmili, C.; Leow, C.C.; De Palma, M. Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Rep. 2014, 8, 696–706. [Google Scholar] [CrossRef] [Green Version]
- Zhu, J.; Bilan, P.J.; Moyers, J.S.; Antonetti, D.A.; Kahn, C.R. Rad, a novel Ras-related GTPase, interacts with skeletal muscle beta-tropomyosin. J. Biol. Chem. 1996, 271, 768–773. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Taulés, M.; Rius, E.; Talaya, D.; López-Girona, A.; Bachs, O.; Agell, N. Calmodulin is essential for cyclin-dependent kinase 4 (Cdk4) activity and nuclear accumulation of cyclin D1-Cdk4 during G1. J. Biol. Chem. 1998, 273, 33279–33286. [Google Scholar] [CrossRef] [Green Version]
- Manstein, D.J.; Mulvihill, D.P. Tropomyosin-Mediated Regulation of Cytoplasmic Myosins. Traffic 2016, 17, 872–877. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mayanagi, T.; Sobue, K. Diversification of caldesmon-linked actin cytoskeleton in cell motility. Cell Adh. Migr. 2011, 5, 150–159. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kantor, J.D.; McCormick, B.; Steeg, P.S.; Zetter, B.R. Inhibition of cell motility after nm23 transfection of human and murine tumor cells. Cancer Res. 1993, 53, 1971–1973. [Google Scholar]
- Falandry, C.; Bonnefoy, M.; Freyer, G.; Gilson, E. Biology of cancer and aging: A complex association with cellular senescence. J. Clin. Oncol. 2014, 32, 2604–2610. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sun, Y.; Campisi, J.; Higano, C.; Beer, T.M.; Porter, P.; Coleman, I.; True, L.; Nelson, P.S. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat. Med. 2012, 18, 1359–1368. [Google Scholar] [CrossRef] [Green Version]
- Demaria, M.; O’Leary, M.N.; Chang, J.; Shao, L.; Liu, S.; Alimirah, F.; Koenig, K.; Le, C.; Mitin, N.; Deal, A.M.; et al. Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov. 2017, 7, 165–176. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lujambio, A. To clear, or not to clear (senescent cells)? That is the question. Bioessays 2016, 38 (Suppl. S1), S56–S64. [Google Scholar] [CrossRef]
- Wiley, C.D.; Campisi, J. From Ancient Pathways to Aging Cells-Connecting Metabolism and Cellular Senescence. Cell Metab. 2016, 23, 1013–1021. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Alexander, K.; Hinds, P.W. Requirement for p27(KIP1) in retinoblastoma protein-mediated senescence. Mol. Cell Biol. 2001, 21, 3616–3631. [Google Scholar] [CrossRef] [Green Version]
- Stein, G.H.; Beeson, M.; Gordon, L. Failure to phosphorylate the retinoblastoma gene product in senescent human fibroblasts. Science 1990, 249, 666–669. [Google Scholar] [CrossRef] [PubMed]
Tumor Type | Models | Pathway | Function | Refs. |
---|---|---|---|---|
Liver | Hepatic cancer patient specimen | P53/RRAD/ACTG1 | low expression levels of RRAD are significantly correlated to large tumor size, advanced tumor stage and bad prognosis. | [13] |
Human hepatocellular carcinoma cell lines | ||||
Nude mice | ||||
Wild type and S47 E1A/RAS transformed mouse embryo fibroblast lines | P53/RRAD/GLUT 1 | Low RRAD expression levels significantly increase GLUT1 in S47 tumor cells with increased risk for hepatocellular carcinoma and other cancers. | [14] | |
Human hepatocellular carcinoma cell lines | RRAD inhibits cell proliferation and migration, arrests the cell cycle and increases apoptosis. | [15] | ||
Hepatic cancer patient specimen | ||||
nude mice | ||||
Human hepatocellular carcinoma cell lines | RRAD/GLUT 1, HK-II | low expression of RRAD was associated with tumor size, microvascular invasion or metastasis, and tumor node metastasis (TNM) stage. | [16] | |
Hepatic cancer patient specimen | ||||
Nasopharynx | NPC patient specimen | Hypermethylation | RRAD is hypermethylated in nasopharyngeal carcinoma cell. Low expression levels of RRAD induce proliferation, colony formation, and migration. | [17,18] |
NPC cell lines | ||||
Lung | NSCLC patient specimen | DUXAP10/ LSD1/RRAD | DUXAP10 downregulates RRAD through binding with LSD1 could promote the cell cycle progression and proliferation phenotype of NSCLC cells. | [19] |
NSCLC cell lines | ||||
Lung cancer cell lines | HPV/RRAD/NF-Κb/HIF-1α/GLUT 1 | RRAD downregulates the expression of both HIF-1α and GLUT1. | [20] | |
Lung adenocarcinoma cell lines | RRAD/ NF-κB/ MMP9 | RRAD suppresses MMP9 expression and cell invasion. | [21] | |
Lung cancer cell lines | P53/RRAD/GLUT1 | RRAD greatly reduces glycolysis through inhibition of GLUT1 translocation to the plasma membrane in lung cancer cells. | [22] | |
NSCLC cell lines Adrenal carcinoma cell lines | BRG1(SMARCA4)/ /RRAD | RRAD expression levels decrease in BRG1 mutation NSCLC cells. | [23] | |
NSCLC patient specimen | P53/RRAD/ROCK2/LIMK/ cofilin/actin P53/RRAD/14-3-3/SSH-L1/cofilin/actin Methylation | RRAD promotes the stabilization of actin, inhibit cell migration. | [24] | |
NSCLC cell lines | ||||
31 lung cancer cell lines (20 NSCLC and 11 SCLC cell lines) Non-malignant human bronchial epithelial cells (NHBEC) | Methylation | RRAD methylation suppresses its transcription and affect survival of patients with lung cancer. | [25] | |
Breast | breast cancer cell lines | Methylation | RRAD gene is hypermethylated and silenced in breast cancer patients. | [26] |
nonmalignant human mammary epithelial cells (NHMEC) | ||||
Breast cancer patient specimen | RRAD is frequently downregulated in non-advanced breast cancers | [27] | ||
Cervix | Cervical carcinoma cell lines | Methylation | RRAD gene is hypermethylated and silenced in cervical cancer patients. | [28] |
Cervical patient specimen (with or without HPV) | ||||
Brain | Glioblastoma patient specimen | Hypermethylation | RRAD gene is hypermethylated and silenced in GBM patients and associated with short-term survival. | [29] |
Esophagus | Esophageal carcinoma patient specimens | Hypermethylation | aberrant methylation of RRAD may be involved in pathogenesis of a subset of ESCC. | [30] |
Esophageal adenoma patient specimens | ||||
Ovary | Ovarian cancer cell lines | Ras V12/RRAD | downregulation of RRAD led to an increase in glucose uptake, which may be associated with cancer cell Aerobic glycolysis. | [31] |
Epithelial ovarian cancer cell lines | P53/RRAD | RRAD mRNA level is increased after aspirin acetylates p53. | [32] | |
Mesothelium | Malignant mesothelioma cell lines | Hypermethylation | aberrant methylation of RRAD plays a role in the pathogenesis of MM. | [33] |
Tumor Type | Models | Pathways | Function | Ref. |
---|---|---|---|---|
Brain | Human Glioblastoma cell lines | RTKs(EGFR)/STAT3/RRAD/EEA1 | depletion of RRAD leads to decreased proliferation and survival of GBM cells RRAD is associated with chemotherapy (temozolomide) resistance. RRAD enhances self-renewing ability, tumor sphere formation, EMT, and in vivo tumorigenesis. | [34] |
Human Glioblastoma multiforme cell lines Nude mice | EGFR/STAT3 | Oxelaidin targets RRAD and inhibits EGFR/STAT3 signaling pathway to influence growth, apoptosis, and chemo-resistance of glioblastoma cell lines. | [35] | |
Liver | HCC cell lines (derived from hepatocarcinoma patient specimen) | RRAD expression levels are upregulated in HCC cells and have capacities to promote proliferation and migration. | [36] | |
Bone | Human osteosarcoma cells--U2OS | (p53, NF-κB)/RRAD | RRAD knockdown resulted in increased cellular senescence in U2SO cells. | [37] |
Blood | Human leukemia cell lines | PI3K/Akt/Noxa/Bcl-2 | RRAD promotes the bortezomib/drug resistance. | [38] |
Lymphoma cell line | RRAD enhances resistance to bortezomib-induced apoptosis. | |||
Stomach | Gastric cancer cell lines Gastric cancer patient-derived cells Matched pairs of primary cancer tissue and non-tumor tissue | RRAD/Vimentin, twist, snail, and occludin; RRAD/VEGF, ANGP | RRAD promotes gastric tumor cell proliferation, invasion, EMT and angiogenesis | [39] |
Colorectum | Colorectal cancer cell lines Colorectal cancer patient-derived cells Matched pairs of primary cancer tissue and non-tumor tissue | RRAD/Vimentin, twist, snail, and occludin; RRAD/VEGF, ANGP | RRAD promotes colorectal tumor cell proliferation, invasion, EMT and angiogenesis. | [39] |
Breast | Breast cancer patient specimen Human breast carcinoma cell lines Nude mice | RRAD accelerates growth of breast cancer cells in vitro and increase the tumorigenicity of these cells when injected into nude mice. | [27] | |
Prostate | Prostate cancer cell line-PC-3 and DU145 Athymic nude mice | RRAD/GCIP | RRAD suppresses DNA damage-induced cell cycle arrest and induction of premature senescence. RRAD expression increased doxorubicin resistance. RRAD increases telomerase activity and colony formation. | [30] |
Prostate cancer cell line-LAPC4 | EGR1/RRAD | RRAD is overexpressed in prostate tumors and may promote cancer cell growth as down-stream target gene of EGR1 | [40] | |
Skin | K-1735 TK melanoma cells | RRAD can enhance DNA synthesis in response to serum. | [41] |
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Sun, Z.; Li, Y.; Tan, X.; Liu, W.; He, X.; Pan, D.; Li, E.; Xu, L.; Long, L. Friend or Foe: Regulation, Downstream Effectors of RRAD in Cancer. Biomolecules 2023, 13, 477. https://doi.org/10.3390/biom13030477
Sun Z, Li Y, Tan X, Liu W, He X, Pan D, Li E, Xu L, Long L. Friend or Foe: Regulation, Downstream Effectors of RRAD in Cancer. Biomolecules. 2023; 13(3):477. https://doi.org/10.3390/biom13030477
Chicago/Turabian StyleSun, Zhangyue, Yongkang Li, Xiaolu Tan, Wanyi Liu, Xinglin He, Deyuan Pan, Enmin Li, Liyan Xu, and Lin Long. 2023. "Friend or Foe: Regulation, Downstream Effectors of RRAD in Cancer" Biomolecules 13, no. 3: 477. https://doi.org/10.3390/biom13030477
APA StyleSun, Z., Li, Y., Tan, X., Liu, W., He, X., Pan, D., Li, E., Xu, L., & Long, L. (2023). Friend or Foe: Regulation, Downstream Effectors of RRAD in Cancer. Biomolecules, 13(3), 477. https://doi.org/10.3390/biom13030477