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Extracellular Signals in the Control of Gene Expression Regulating Cellular Survival, Death and Differentiation

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 68199

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Prof. Dr. Claudia Martini

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Dipartimento di Farmacia, Università di Pisa, Pisa, Italy
Interests: neurochemistry; neurodegeneration; signaling: receptors interactions; receptor metabolism; life/death/differentiation signaling; traslocator protein
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Maria Letizia Trincavelli

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Università di Pisa, Dipartimento di Farmacia, Pisa, Italy
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Dr. Simona Daniele

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Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Interests: intracellular pathways; molecular signaling; epigenetic regulation; brain diseases; neurodegeneration; glioblastoma multiforme
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mammalian development and cell fate specification are controlled by various regulatory mechanisms that interact in a coordinated way to guarantee a correct regulation of gene expression. In particular, transcriptional networks can be regulated by extracellular signals, including changes in the microenvironment and mechanical stimuli, to control cell fate decision such as to escape or undergo apoptosis, or to differentiate.

How do cells “read” information from the environment and translate it into specific cell fate decisions? Recent findings suggest that cell fate is encoded in early signaling events and can be predicted from defined signal properties. Specifically, the time course of activated key signaling molecules can be related to cellular fate such as proliferation or differentiation. Nowadays, the identification of the key signal mediators and their linking to cell fate is also facilitated by transcriptomics and proteomics analyses, assisted by bioinformatics and mathematical modeling.

This Special Issue focuses on the recent progress in understanding the biochemical and molecular biology of cellular survival, death and differentiation, considering in particular changes coming from the cellular microenvironment that affect the transcriptional network. Specific changes in gene expression patterns and alterations in the protein expression in cellular or animal models will also be considered in this Special Issue.

Prof. Dr. Claudia Martini
Prof. Dr. Maria Letizia Trincavelli
Dr. Simona Daniele
Guest Editors

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Keywords

cell survival signals
cell death signals
cell differentiation signals
signal transduction
extracellular stimuli
extracellular control of gene expression
cellular fate

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Published Papers (12 papers)

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18 pages, 2545 KiB

Open AccessArticle

In Vitro Effects of Vaspin on Porcine Granulosa Cell Proliferation, Cell Cycle Progression, and Apoptosis by Activation of GRP78 Receptor and Several Kinase Signaling Pathways Including MAP3/1, AKT, and STAT3

by Patrycja Kurowska, Ewa Mlyczyńska, Monika Dawid, Małgorzata Opydo-Chanek, Joelle Dupont and Agnieszka Rak

Int. J. Mol. Sci. 2019, 20(22), 5816; https://doi.org/10.3390/ijms20225816 - 19 Nov 2019

Cited by 31 | Viewed by 4856

Abstract

Vaspin, a visceral adipose tissue-derived serine protease inhibitor, is expressed in the porcine ovary; it induces the activation of various kinases and steroidogenesis. The aim of this study was to examine the effect of vaspin on granulosa (Gc) proliferation, cell cycle regulation, and apoptosis. Porcine Gc was incubated with vaspin (0.01–10 ng/mL) for 24 to 72 h, proliferation was measured using alamarBlue assay, cell cycle progression was assessed using flow cytometry, and cyclin (D, E, and A) protein expression was measured using immunoblotting. Apoptosis was assessed by measuring caspase activity using Caspase-glo 3/7 assay. Furthermore, histone-associated DNA fragments levels were measured using a cell-death detection ELISA; BAX (bcl-2-like protein 4), BCL2 (B-cell lymphoma 2), caspases (-3, -8, and -9), p53 mRNA, and protein expression were assessed using real time PCR and immunoblotting. We found that vaspin significantly enhanced Gc proliferation and cell cycle progression into the S and G2/M phases and decreased apoptosis. We observed that siRNA silencing of the glucose-regulated protein (GRP78) receptor and pharmacological inhibitors of mitogen-activated kinase (MAP3/1/ERK1/2), Janus kinase (STAT3) and protein kinase B (AKT) blocked the ability of vaspin cell proliferation and enhanced caspase-3/7 activities. These results suggest that vaspin via mitogenic effect on porcine Gc acts as a new regulator of ovarian growth, development, or folliculogenesis. Full article

(This article belongs to the Special Issue Extracellular Signals in the Control of Gene Expression Regulating Cellular Survival, Death and Differentiation)

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21 pages, 4671 KiB

Open AccessArticle

Neutrophil Maturation and Survival Is Controlled by IFN-Dependent Regulation of NAMPT Signaling

by Elena Siakaeva, Ekaterina Pylaeva, Ilona Spyra, Sharareh Bordbari, Benedikt Höing, Cornelius Kürten, Stephan Lang and Jadwiga Jablonska

Int. J. Mol. Sci. 2019, 20(22), 5584; https://doi.org/10.3390/ijms20225584 - 8 Nov 2019

Cited by 16 | Viewed by 5156

Abstract

Granulocyte-colony stimulating factor (G-CSF)/nicotinamide phosphoribosyltransferase (NAMPT) signaling has been shown to be crucial for the modulation of neutrophil development and functionality. As this signaling pathway is significantly suppressed by type I interferons (IFNs), we aimed to study how the regulation of neutrophil differentiation and phenotype is altered in IFN-deficient mice during granulopoiesis. The composition of bone marrow granulocyte progenitors and their Nampt expression were assessed in bone marrow of type I IFN receptor knockout (Ifnar1^-/-) mice and compared to wild-type animals. The impact of NAMPT inhibition on the proliferation, survival, and differentiation of murine bone marrow progenitors, as well as of murine 32D and human HL-60 neutrophil-like cell lines, was estimated. The progressive increase of Nampt expression during neutrophil progenitor maturation could be observed, and it was more prominent in IFN-deficient animals. Altered composition of bone marrow progenitors in these mice correlated with the dysregulation of apoptosis and altered differentiation of these cells. We observed that NAMPT is vitally important for survival of early progenitors, while at later stages it delays the differentiation of neutrophils, with moderate effect on their survival. This study shows that IFN-deficiency leads to the elevated NAMPT expression in the bone marrow, which in turn modulates neutrophil development and differentiation, even in the absence of tumor-derived stimuli. Full article

(This article belongs to the Special Issue Extracellular Signals in the Control of Gene Expression Regulating Cellular Survival, Death and Differentiation)

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12 pages, 2810 KiB

Open AccessArticle

IGF-1 Inhibits Apoptosis of Porcine Primary Granulosa Cell by Targeting Degradation of Bim_EL

by Ying Han, Shumin Wang, Yingzheng Wang and Shenming Zeng

Int. J. Mol. Sci. 2019, 20(21), 5356; https://doi.org/10.3390/ijms20215356 - 28 Oct 2019

Cited by 20 | Viewed by 4760

Abstract

Insulin-like growth factor-1 (IGF-1) is an intra-ovarian growth factor that plays important endocrine or paracrine roles during ovarian development. IGF-1 affects ovarian function and female fertility through reducing apoptosis of granulosa cells, yet the underlying mechanism remains poorly characterized. Here, we aimed to address these knowledge gaps using porcine primary granulosa cells and examining the anti-apoptotic mechanisms of IGF-1. IGF-1 prevented the granulosa cell from apoptosis, as shown by TUNEL and Annexin V/PI detection, and gained the anti-apoptotic index, the ratio of Bcl-2/Bax. This process was partly mediated by reducing the pro-apoptotic Bim_EL (Bcl-2 Interacting Mediator of Cell Death-Extra Long) protein level. Western blotting showed that IGF-1 promoted Bim_EL phosphorylation through activating p-ERK1/2, and that the proteasome system was responsible for degradation of phosphorylated Bim_EL. Meanwhile, IGF-1 enhanced the Beclin1 level and the rate of LC3 II/LC3 I, indicating that autophagy was induced by IGF-1. By blocking the proteolysis processes of both proteasome and autophagy flux with MG132 and chloroquine, respectively, the Bim_EL did not reduce and the phosphorylated Bim_EL protein accumulated, thereby indicating that both proteasome and autophagy pathways were involved in the degradation of Bim_EL stimulated by IGF-1. In conclusion, IGF-1 inhibited porcine primary granulosa cell apoptosis via degradation of pro-apoptotic Bim_EL. This study is critical for us to further understand the mechanisms of follicular survival and atresia regulated by IGF-1. Moreover, it provides a direction for the treatment of infertility caused by ovarian dysplasia, such as polycystic ovary syndrome and the improvement of assisted reproductive technology. Full article

(This article belongs to the Special Issue Extracellular Signals in the Control of Gene Expression Regulating Cellular Survival, Death and Differentiation)

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18 pages, 12951 KiB

Open AccessArticle

Inhibition of Ihh Reverses Temporomandibular Joint Osteoarthritis via a PTH1R Signaling Dependent Mechanism

by Hongxu Yang, Mian Zhang, Qian Liu, Hongyun Zhang, Jing Zhang, Lei Lu, Mianjiao Xie, Di Chen and Meiqing Wang

Int. J. Mol. Sci. 2019, 20(15), 3797; https://doi.org/10.3390/ijms20153797 - 3 Aug 2019

Cited by 40 | Viewed by 4320

Abstract

The temporomandibular joint (TMJ), which is biomechanically related to dental occlusion, is often insulted by osteoarthritis (OA). This study was conducted to clarify the relationship between Indian hedgehog (Ihh) and parathyroid hormone receptor 1 (PTH1R) signaling in modulating the enhanced chondrocyte terminal differentiation in dental stimulated TMJ osteoarthritic cartilage. A gain- and loss-of-function strategy was used in an in vitro model in which fluid flow shear stress (FFSS) was applied, and in an in vivo model in which the unilateral anterior cross-bite (UAC) stimulation was adopted. Ihh and PTH1R signaling was modulated through treating the isolated chondrocytes with inhibitor/activator and via deleting Smoothened (Smo) and/or Pth1r genes in mice with the promoter gene of type 2 collagen (Col2-CreER) in the tamoxifen-inducible pattern. We found that both FFSS and UAC stimulation promoted the deep zone chondrocytes to undergo terminal differentiation, while cells in the superficial zone were robust. We demonstrated that the terminal differentiation process in deep zone chondrocytes promoted by FFSS and UAC was mediated by the enhanced Ihh signaling and declined PTH1R expression. The FFSS-promoted terminal differentiation was suppressed by administration of the Ihh inhibitor or PTH1R activator. The UAC-promoted chondrocytes terminal differentiation and OA-like lesions were rescued in Smo knockout, but were enhanced in Pth1r knockout mice. Importantly, the relieving effect of Smo knockout mice was attenuated when Pth1r knockout was also applied. Our data suggest a chondrocyte protective effect of suppressing Ihh signaling in TMJ OA cartilage which is dependent on PTH1R signaling. Full article

(This article belongs to the Special Issue Extracellular Signals in the Control of Gene Expression Regulating Cellular Survival, Death and Differentiation)

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17 pages, 5464 KiB

Open AccessArticle

Plasticity of High-Density Neutrophils in Multiple Myeloma is Associated with Increased Autophagy Via STAT3

by Fabrizio Puglisi, Nunziatina Laura Parrinello, Cesarina Giallongo, Daniela Cambria, Giuseppina Camiolo, Claudia Bellofiore, Concetta Conticello, Vittorio Del Fabro, Valerio Leotta, Uros Markovic, Giuseppe Sapienza, Alessandro Barbato, Silvia Scalese, Daniele Tibullo, Maria Violetta Brundo, Giuseppe Alberto Palumbo, Francesco Di Raimondo and Alessandra Romano

Int. J. Mol. Sci. 2019, 20(14), 3548; https://doi.org/10.3390/ijms20143548 - 19 Jul 2019

Cited by 19 | Viewed by 5331

Abstract

In both monoclonal gammopathy of uncertain significance (MGUS) and multiple myeloma (MM) patients, immune functions are variably impaired, and there is a high risk of bacterial infections. Neutrophils are the most abundant circulating leukocytes and constitute the first line of host defense. Since little is known about the contribution of autophagy in the neutrophil function of MGUS and MM patients, we investigated the basal autophagy flux in freshly sorted neutrophils of patients and tested the plastic response of healthy neutrophils to soluble factors of MM. In freshly sorted high-density neutrophils obtained from patients with MGUS and MM or healthy subjects, we found a progressive autophagy trigger associated with soluble factors circulating in both peripheral blood and bone marrow, associated with increased IFNγ and pSTAT3S727. In normal high-density neutrophils, the formation of acidic vesicular organelles, a morphological characteristic of autophagy, could be induced after exposure for three hours with myeloma conditioned media or MM sera, an effect associated with increased phosphorylation of STAT3-pS727 and reverted by treatment with pan-JAK2 inhibitor ruxolitinib. Taken together, our data suggest that soluble factors in MM can trigger contemporary JAK2 signaling and autophagy in neutrophils, targetable with ruxolitinib. Full article

(This article belongs to the Special Issue Extracellular Signals in the Control of Gene Expression Regulating Cellular Survival, Death and Differentiation)

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16 pages, 9579 KiB

Open AccessArticle

Fibronectin Promotes Cell Growth and Migration in Human Renal Cell Carcinoma Cells

by Yen-Chuan Ou, Jian-Ri Li, Jiaan-Der Wang, Cheng-Yi Chang, Chih-Cheng Wu, Wen-Ying Chen, Yu-Hsiang Kuan, Su-Lan Liao, Hsi-Chi Lu and Chun-Jung Chen

Int. J. Mol. Sci. 2019, 20(11), 2792; https://doi.org/10.3390/ijms20112792 - 7 Jun 2019

Cited by 34 | Viewed by 4840

Abstract

The prognostic and therapeutic values of fibronectin have been reported in patients with renal cell carcinoma (RCC). However, the underlying mechanisms of malignancy in RCC are not completely understood. We found that silencing of fibronectin expression attenuated human RCC 786-O and Caki-1 cell growth and migration. Silencing of potential fibronectin receptor integrin α5 and integrin β1 decreased 786-O cell ability in movement and chemotactic migration. Biochemical examination revealed a reduction of cyclin D1 and vimentin expression, transforming growth factor-β1 (TGF-β1) production, as well as Src and Smad phosphorylation in fibronectin-silenced 786-O and Caki-1 cells. Pharmacological inhibition of Src decreased 786-O cell growth and migration accompanied by a reduction of cyclin D1, fibronectin, vimentin, and TGF-β1 expression, as well as Src and Smad phosphorylation. In 786-O cells, higher activities in cell growth and migration than in Caki-1 cells were noted, along with elevated fibronectin and TGF-β1 expression. The additions of exogenous fibronectin and TGF-β1 promoted Caki-1 cell growth and migration, and increased cyclin D1, fibronectin, vimentin, and TGF-β1 expression, as well as Src and Smad phosphorylation. These findings highlight the role of fibronectin in RCC cell growth and migration involving Src and TGF-β1 signaling. Full article

(This article belongs to the Special Issue Extracellular Signals in the Control of Gene Expression Regulating Cellular Survival, Death and Differentiation)

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18 pages, 2758 KiB

Open AccessArticle

RSK2-Mediated ELK3 Activation Enhances Cell Transformation and Breast Cancer Cell Growth by Regulation of c-fos Promoter Activity

by Sun-Mi Yoo, Cheol-Jung Lee, Hyun-Jung An, Joo Young Lee, Hye Suk Lee, Han Chang Kang, Sung-Jun Cho, Seung-Min Kim, Juhee Park, Dae Joon Kim and Yong-Yeon Cho

Int. J. Mol. Sci. 2019, 20(8), 1994; https://doi.org/10.3390/ijms20081994 - 23 Apr 2019

Cited by 21 | Viewed by 5059

Abstract

Ribosomal S6 kinase 2 (RSK2), regulated by Ras/Raf/MEKs/ERKs, transmits upstream activation signals to downstream substrates including kinases and transcription and epigenetic factors. We observed that ELK members, including ELK1, 3, and 4, highly interacted with RSK2. We further observed that the RSK2-ELK3 interaction was mediated by N-terminal kinase and linker domains of RSK2, and the D and C domains of ELK3, resulting in the phosphorylation of ELK3. Importantly, RSK2-mediated ELK3 enhanced c-fos promoter activity. Notably, chemical inhibition of RSK2 signaling using kaempferol (a RSK2 inhibitor) or U0126 (a selective MEK inhibitor) suppressed EGF-induced c-fos promoter activity. Moreover, functional deletion of RSK2 by knockdown or knockout showed that RSK2 deficiency suppressed EGF-induced c-fos promoter activity, resulting in inhibition of AP-1 transactivation activity and Ras-mediated foci formation in NIH3T3 cells. Immunocytofluorescence assay demonstrated that RSK2 deficiency reduced ELK3 localization in the nucleus. In MDA-MB-231 breast cancer cells, knockdown of RSK2 or ELK3 suppressed cell proliferation with accumulation at the G1 cell cycle phase, resulting in inhibition of foci formation and anchorage-independent cancer colony growth in soft agar. Taken together, these results indicate that a novel RSK2/ELK3 signaling axis, by enhancing c-Fos-mediated AP-1 transactivation activity, has an essential role in cancer cell proliferation and colony growth. Full article

(This article belongs to the Special Issue Extracellular Signals in the Control of Gene Expression Regulating Cellular Survival, Death and Differentiation)

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11 pages, 3643 KiB

Open AccessArticle

Involvement of Gastrin-Releasing Peptide Receptor in the Regulation of Adipocyte Differentiation in 3T3-L1 Cells

by Mi-Kyoung Kim, Hyun-Joo Park, Yeon Kim, Soo-Kyung Bae, Hyung Joon Kim and Moon-Kyoung Bae

Int. J. Mol. Sci. 2018, 19(12), 3971; https://doi.org/10.3390/ijms19123971 - 10 Dec 2018

Cited by 3 | Viewed by 4585

Abstract

Gastrin-releasing peptide (GRP), a member of bombesin-like peptides, and its receptor (GRP-R) play an important role in various physiological and pathological conditions. In this work, we investigated the role of GRP-R on adipogenesis in 3T3-L1 adipocytes. The expression of GRP-R was significantly increased during the adipocyte differentiation of 3T3-L1 cells. The inhibition of GRP-R by the antagonist RC-3095 affected adipogenesis in 3T3-L1 cells, which reduced lipid accumulation and regulated the expression of adipogenic genes. Moreover, cyclic AMP response element-binding protein (CREB) directly bound to the GRP-R promoter upon exposure to adipogenic stimuli. The down-regulation of GRP-R by the knockdown of CREB inhibited adipocyte differentiation of 3T3-L1 cells. Together these results suggest that the regulation of GRP-R activity or expression has an influence on adipogenesis through regulating adipogenic related genes. Full article

(This article belongs to the Special Issue Extracellular Signals in the Control of Gene Expression Regulating Cellular Survival, Death and Differentiation)

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13 pages, 2467 KiB

Open AccessArticle

Activation of CREBZF Increases Cell Apoptosis in Mouse Ovarian Granulosa Cells by Regulating the ERK1/2 and mTOR Signaling Pathways

by Fenglei Chen, Xin Wen, Pengfei Lin, Huatao Chen, Aihua Wang and Yaping Jin

Int. J. Mol. Sci. 2018, 19(11), 3517; https://doi.org/10.3390/ijms19113517 - 8 Nov 2018

Cited by 13 | Viewed by 3716

Abstract

CREBZF, a multifunction transcriptional regulator, participates in the regulation of numerous cellular functions. The aims of the present study were to detect the localization of CREBZF expression in the ovary and explore the role of CREBZF and related mechanisms in the apoptosis of ovarian granulosa cells. We found by immunohistochemistry that CREBZF was mainly located in granulosa cells and oocytes during the estrous cycle. Western blot analysis showed that SMILE was the main isoform of CREBZF in the ovary. The relationship between apoptosis and CREBZF was assessed via CREBZF overexpression and knockdown. Flow cytometry analysis showed that CREBZF induced cell apoptosis in granulosa cells. Western bolt analysis showed that overexpression of CREBZF upregulated BAX and cleaved Caspase-3, while it downregulated BCL-2. Furthermore, overexpression of CREBZF inhibited the ERK1/2 and mTOR signaling pathways through the phosphorylation of intracellular-regulated kinases 1/2 (ERK1/2) and p70 S6 kinase (S6K1). Moreover, we found that CREBZF also activated autophagy by increasing LC3-II. In summary, these results suggest that CREBZF might play a proapoptotic role in cell apoptosis in granulosa cells, possibly by regulating the ERK1/2 and mTOR signaling pathways. Full article

(This article belongs to the Special Issue Extracellular Signals in the Control of Gene Expression Regulating Cellular Survival, Death and Differentiation)

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16 pages, 3230 KiB

Open AccessArticle

Exosomes Secreted from Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Accelerate Skin Cell Proliferation

by Soo Kim, Seul Ki Lee, Hyunjung Kim and Tae Min Kim

Int. J. Mol. Sci. 2018, 19(10), 3119; https://doi.org/10.3390/ijms19103119 - 11 Oct 2018

Cited by 158 | Viewed by 12149

Abstract

Induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (iMSCs) serve as a unique source for cell therapy. We investigated whether exosomes from iMSCs promote the proliferation of human keratinocytes (HaCaT) and human dermal fibroblasts (HDFs). iPSCs were established from human Wharton’s jelly MSCs and were allowed to differentiate into iMSCs. Exosomes were collected from the culture supernatant of MSCs (MSC-exo) and iMSCs (iMSC-exo), and their characteristics were investigated. Both exosome types possessed basic characteristics of exosomes and were taken up by skin cells in vitro and in vivo. A significant increase in HaCaT proliferation was observed with iMSC-exo, although both exosomes increased the viability and cell cycle progression in HaCaT and HDFs. No significant difference was observed in the closure of wound scratch and the expression of reparative genes between cells treated with the two exosome types. Both exosomes enhanced the secretion of collagen in HaCaT and HDFs; however, an increase in fibronectin level was observed only in HaCaT, and this effect was better with iMSC-exo treatment. Only iMSC-exo increased the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2. Our results indicate that iMSC-exo promote the proliferation of skin cells by stimulating ERK1/2 and highlight the application of iMSCs for producing exosomes. Full article

(This article belongs to the Special Issue Extracellular Signals in the Control of Gene Expression Regulating Cellular Survival, Death and Differentiation)

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Review

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14 pages, 1016 KiB

Open AccessReview

Elimination of Osteosarcoma by Necroptosis with Graphene Oxide-Associated Anti-HER2 Antibodies

by Hongmei Xiao, Peter E. Jensen and Xinjian Chen

Int. J. Mol. Sci. 2019, 20(18), 4360; https://doi.org/10.3390/ijms20184360 - 5 Sep 2019

Cited by 26 | Viewed by 6448

Abstract

The prognosis for non-resectable or recurrent osteosarcoma (OS) remains poor. The finding that the majority of OS overexpress the protooncogene HER2 raises the possibility of using HER2 as a therapeutic target. However, clinical trials on the anti-HER2 antibody trastuzumab (TRA) in treating OS find no therapeutic benefit. HER2 overexpression in OS is not generally associated with gene amplification, with low-level expression regarded as HER2 “negative”, as per criteria used to classify breast cancer HER2 status. Nevertheless, active HER2-targeting approaches, such as virus-based HER2 vaccines or CAR-T cells have generated promising results. More recently, it has been found that the noncovalent association of TRA with nanomaterial graphene oxide (GO) generates stable TRA/GO complexes capable of rapidly killing OS cells. TRA/GO induces oxidative stress and strong HER2 signaling to elicit immediate degradation of both cIAP (cellular inhibitor of apoptosis protein) and caspase 8, leading to activation of necroptosis. This is an attractive mechanism of cancer cell death as chemo/apoptosis-resistant tumors may remain susceptible to necroptosis. In addition, necroptosis is potentially immunogenic to promote tumor immunity, as opposed to apoptosis that tends to silence tumor immunity. Currently, no established anticancer therapeutics are known to eliminate cancers by necroptosis. The aim of this article is to review the rationale and mechanisms of TRA/GO-mediated cytotoxicity. Full article

(This article belongs to the Special Issue Extracellular Signals in the Control of Gene Expression Regulating Cellular Survival, Death and Differentiation)

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11 pages, 1520 KiB

Open AccessReview

All-trans Retinoic Acid as a Versatile Cytosolic Signal Modulator Mediated by CRABP1

by Isha Nagpal and Li-Na Wei

Int. J. Mol. Sci. 2019, 20(15), 3610; https://doi.org/10.3390/ijms20153610 - 24 Jul 2019

Cited by 32 | Viewed by 5911

Abstract

All-trans retinoic acid (AtRA), an active metabolite of vitamin A, is recognized for its classical action as an endocrine hormone that triggers genomic effects mediated through nuclear receptors RA receptors (RARs). New evidence shows that atRA-mediated cellular responses are biphasic with rapid and delayed responses. Most of these rapid atRA responses are the outcome of its binding to cellular retinoic acid binding protein 1 (CRABP1) that is predominantly localized in cytoplasm and binds to atRA with a high affinity. This review summarizes the most recent studies of such non-genomic outcomes of atRA and the role of CRABP1 in mediating such rapid effects in different cell types. In embryonic stem cells (ESCs), atRA-CRABP1 dampens growth factor sensitivity and stemness. In a hippocampal neural stem cell (NSC) population, atRA-CRABP1 negatively modulates NSC proliferation and affects learning and memory. In cardiomyocytes, atRA-CRABP1 prevents over-activation of calcium-calmodulin-dependent protein kinase II (CaMKII), protecting heart function. These are supported by the fact that CRABP1 gene knockout (KO) mice exhibit multiple phenotypes including hippocampal NSC expansion and spontaneous cardiac hypertrophy. This indicates that more potential processes/signaling pathways involving atRA-CRABP1 may exist, which remain to be identified. Full article

(This article belongs to the Special Issue Extracellular Signals in the Control of Gene Expression Regulating Cellular Survival, Death and Differentiation)

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