International Journal of Molecular Sciences

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19 pages, 3191 KiB

Open AccessArticle

Cirsiliol Suppressed Epithelial to Mesenchymal Transition in B16F10 Malignant Melanoma Cells through Alteration of the PI3K/Akt/NF-κB Signaling Pathway

by Priyanka Prasad, Andrea Vasas, Judit Hohmann, Anupam Bishayee and Dona Sinha

Int. J. Mol. Sci. 2019, 20(3), 608; https://doi.org/10.3390/ijms20030608 - 31 Jan 2019

Cited by 35 | Viewed by 5316

Abstract

Malignant melanoma is a highly aggressive form of skin cancer which has a propensity for metastasis. Epithelial mesenchymal transition (EMT) plays a primordial role in the progression of metastatic disease. Metastatic melanoma is resistant to conventional therapies. Hence, researchers have been exploring alternative [...] Read more.

Malignant melanoma is a highly aggressive form of skin cancer which has a propensity for metastasis. Epithelial mesenchymal transition (EMT) plays a primordial role in the progression of metastatic disease. Metastatic melanoma is resistant to conventional therapies. Hence, researchers have been exploring alternative approaches, including the utility of bioactive phytochemicals to manage metastatic disease. In the present study, we investigated the potential of cirsiliol, a flavonoid isolated from Centaurea jacea L., in modulating the aggressive behavior of B16F10 metastatic melanoma cells, including EMT, and associated molecular mechanisms of action. Cirsiliol was found to be effective in restraining the colony formation and migration of fibronectin-induced B16F10 metastatic melanoma cells. Cirsiliol inhibited the activity and expression of matrix metalloproteinase-9 (MMP-9). Cirsiliol also suppressed the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (also known as Akt)/nuclear factor-κB (NF-κB) signaling pathway which, in turn, caused upregulation of E-cadherin and downregulation of N-cadherin, Snail and Twist. Based on these results, cirsiliol may be considered a promising compound against EMT in the therapeutic management of malignant melanoma. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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11 pages, 1937 KiB

Open AccessArticle

IL-1β Inflammatory Cytokine-Induced TP63 Isoform ∆NP63α Signaling Cascade Contributes to Cisplatin Resistance in Human Breast Cancer Cells

by Mónica G. Mendoza-Rodríguez, Jorge T. Ayala-Sumuano, Lázaro García-Morales, Horacio Zamudio-Meza, Eloy A. Pérez-Yepez and Isaura Meza

Int. J. Mol. Sci. 2019, 20(2), 270; https://doi.org/10.3390/ijms20020270 - 11 Jan 2019

Cited by 33 | Viewed by 5577

Abstract

The mechanisms behind the induction of malignancy and chemoresistance in breast cancer cells are still not completely understood. Inflammation is associated with the induction of malignancy in different types of cancer and is highlighted as an important factor for chemoresistance. In previous work, [...] Read more.

The mechanisms behind the induction of malignancy and chemoresistance in breast cancer cells are still not completely understood. Inflammation is associated with the induction of malignancy in different types of cancer and is highlighted as an important factor for chemoresistance. In previous work, we demonstrated that the inflammatory cytokine interleukin 1β (IL-1β)-induced upregulation of genes was associated with chemoresistance in breast cancer cells. Here, we evaluated the participation and the expression profile of TP63 in the induction of resistance to cisplatin. By loss-of-function assays, we identified that IL-1β particularly upregulates the expression of the tumor protein 63 (TP63) isoform ΔNP63α, through the activation of the IL-1β/IL-1RI/β-catenin signaling pathway. Upregulation of ΔNP63α leads to an increase in the expression of the cell survival factors epidermal growth factor receptor (EGFR) and phosphatase 1D (Wip1), and a decrease in the DNA damage sensor, ataxia-telangiectasia mutated (ATM). The participation of these processes in the increase of resistance to cisplatin was confirmed by silencing TP63 expression or by inhibition of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) activity in the IL-1β/IL-1RI/β-catenin signaling pathway. These data reinforced the importance of an inflammatory environment in the induction of drug resistance in cancer cells and uncovered a molecular mechanism where the IL-1β signaling pathway potentiates the acquisition of cisplatin resistance in breast cancer cells. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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11 pages, 2312 KiB

Open AccessArticle

Gemcitabine Induces Microvesicle Particle Release in a Platelet-Activating Factor-Receptor-Dependent Manner via Modulation of the MAPK Pathway in Pancreatic Cancer Cells

by Anita Thyagarajan, Sayali M. Kadam, Langni Liu, Lisa E. Kelly, Christine M. Rapp, Yanfang Chen and Ravi P. Sahu

Int. J. Mol. Sci. 2019, 20(1), 32; https://doi.org/10.3390/ijms20010032 - 21 Dec 2018

Cited by 20 | Viewed by 3862

Abstract

Studies, including ours, have shown that pro-oxidative stressors, such as chemotherapeutic agents, generate oxidized lipids with agonistic platelet-activating factor (PAF) activity. Importantly, recent reports have implicated that these PAF-agonists are transported extracellularly via microvesicle particles (MVPs). While the role of PAF-receptor (PAF-R) has [...] Read more.

Studies, including ours, have shown that pro-oxidative stressors, such as chemotherapeutic agents, generate oxidized lipids with agonistic platelet-activating factor (PAF) activity. Importantly, recent reports have implicated that these PAF-agonists are transported extracellularly via microvesicle particles (MVPs). While the role of PAF-receptor (PAF-R) has been implicated in mediating chemotherapy effects, its significance in chemotherapy-mediated MVP release in pancreatic cancer has not been studied. The current studies determined the functional significance of PAF-R in gemcitabine chemotherapy-mediated MVP release in human pancreatic cancer cells. Using PAF-R-expressing (PANC-1) and PAF-R-deficient (Hs766T) cells, we demonstrate that gemcitabine induces MVP release in a PAF-R-dependent manner. Blocking of PAF-R via PAF-R antagonist or inhibition of MVP generation via inhibitor of acid sphingomyelinase (aSMase) enzyme, significantly attenuated gemcitabine-mediated MVP release from PANC-1 cells, however, exerted no effects in Hs766T cells. Notably, MVPs from gemcitabine-treated PANC-1 cells, contained a measurable amount of PAF-agonists. Mechanistically, pretreatment with ERK1/2 or p38 inhibitors significantly abrogated gemcitabine-mediated MVP release, indicating the involvement of mitogen-activated protein kinase (MAPK) pathway in PAF-R-dependent gemcitabine-mediated MVP release. These findings demonstrate the significance of PAF-R in gemcitabine-mediated MVP release, as well as the rationale of evaluating PAF-R targeting agents with gemcitabine against pancreatic cancer. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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20 pages, 3147 KiB

Open AccessArticle

HPV-18 E6 Oncoprotein and Its Spliced Isoform E6*I Regulate the Wnt/β-Catenin Cell Signaling Pathway through the TCF-4 Transcriptional Factor

by J. Omar Muñoz-Bello, Leslie Olmedo-Nieva, Leonardo Josué Castro-Muñoz, Joaquín Manzo-Merino, Adriana Contreras-Paredes, Claudia González-Espinosa, Alejandro López-Saavedra and Marcela Lizano

Int. J. Mol. Sci. 2018, 19(10), 3153; https://doi.org/10.3390/ijms19103153 - 13 Oct 2018

Cited by 15 | Viewed by 4116

Abstract

The Wnt/β-catenin signaling pathway regulates cell proliferation and differentiation and its aberrant activation in cervical cancer has been described. Persistent infection with high risk human papillomavirus (HR-HPV) is the most important factor for the development of this neoplasia, since E6 and E7 viral [...] Read more.

The Wnt/β-catenin signaling pathway regulates cell proliferation and differentiation and its aberrant activation in cervical cancer has been described. Persistent infection with high risk human papillomavirus (HR-HPV) is the most important factor for the development of this neoplasia, since E6 and E7 viral oncoproteins alter cellular processes, promoting cervical cancer development. A role of HPV-16 E6 in Wnt/β-catenin signaling has been proposed, although the participation of HPV-18 E6 has not been previously studied. The aim of this work was to investigate the participation of HPV-18 E6 and E6*I, in the regulation of the Wnt/β-catenin signaling pathway. Here, we show that E6 proteins up-regulate TCF-4 transcriptional activity and promote overexpression of Wnt target genes. In addition, it was demonstrated that E6 and E6*I bind to the TCF-4 (T cell factor 4) and β-catenin, impacting TCF-4 stabilization. We found that both E6 and E6*I proteins interact with the promoter of Sp5, in vitro and in vivo. Moreover, although differences in TCF-4 transcriptional activation were found among E6 intratype variants, no changes were observed in the levels of regulated genes. Furthermore, our data support that E6 proteins cooperate with β-catenin to promote cell proliferation. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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8 pages, 5349 KiB

Open AccessCommunication

Systemic Platelet-Activating Factor-Receptor Agonism Enhances Non-Melanoma Skin Cancer Growth

by Eric Romer, Anita Thyagarajan, Smita Krishnamurthy, Christine M. Rapp, Langni Liu, Katherine Fahy, Azeezat Awoyemi and Ravi P. Sahu

Int. J. Mol. Sci. 2018, 19(10), 3109; https://doi.org/10.3390/ijms19103109 - 11 Oct 2018

Cited by 4 | Viewed by 3581

Abstract

Platelet-activating factor-receptor (PAF-R) agonists are pleiotropic lipid factors that influence multiple biological processes, including the induction and resolution of inflammation as well as immunosuppression. PAF-R agonists have been shown to modulate tumorigenesis and/or tumor growth in various skin cancer models by suppressing either [...] Read more.

Platelet-activating factor-receptor (PAF-R) agonists are pleiotropic lipid factors that influence multiple biological processes, including the induction and resolution of inflammation as well as immunosuppression. PAF-R agonists have been shown to modulate tumorigenesis and/or tumor growth in various skin cancer models by suppressing either cutaneous inflammation and/or anti-tumoral adaptive immunity. We have previously shown that a chronic systemic PAF-R agonist administration of mice enhances the growth of subcutaneously implanted melanoma tumors. Conversely, chronic topical applications of a PAF-R agonist suppressed non-melanoma skin cancer (NMSC) in a topical chemical carcinogenesis model (dimethylbenz[a]anthracene/phorbol 12-myristate 13-acetate (DMBA/PMA)) in-part via anti-inflammatory effects. These results indicate that the context of PAF-R agonist exposure via either chronic cutaneous or systemic administration, result in seemingly disparate effects on tumor promotion. To further dissect the contextual role of PAF-R agonism on tumorigenesis, we chronically administered systemic PAF-R agonist, carbamoyl-PAF (CPAF) to mice under a cutaneous chemical carcinogenesis protocol, recently characterized to initiate both NMSC and melanocytic nevus formation that can progress to malignant melanoma. Our results showed that while systemic CPAF did not modulate melanocytic nevus formation, it enhanced the growth of NMSC tumors. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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20 pages, 2736 KiB

Open AccessArticle

Cytosolic 5′-Nucleotidase II Silencing in a Human Lung Carcinoma Cell Line Opposes Cancer Phenotype with a Concomitant Increase in p53 Phosphorylation

by Rossana Pesi, Edoardo Petrotto, Laura Colombaioni, Simone Allegrini, Mercedes Garcia-Gil, Marcella Camici, Lars Petter Jordheim and Maria Grazia Tozzi

Int. J. Mol. Sci. 2018, 19(7), 2115; https://doi.org/10.3390/ijms19072115 - 20 Jul 2018

Cited by 13 | Viewed by 3446

Abstract

Purine homeostasis is maintained by a purine cycle in which the regulated member is a cytosolic 5′-nucleotidase II (cN-II) hydrolyzing IMP and GMP. Its expression is particularly high in proliferating cells, indeed high cN-II activity or expression in hematological malignancy has been associated [...] Read more.

Purine homeostasis is maintained by a purine cycle in which the regulated member is a cytosolic 5′-nucleotidase II (cN-II) hydrolyzing IMP and GMP. Its expression is particularly high in proliferating cells, indeed high cN-II activity or expression in hematological malignancy has been associated to poor prognosis and chemoresistance. Therefore, a strong interest has grown in developing cN-II inhibitors, as potential drugs alone or in combination with other compounds. As a model to study the effect of cN-II inhibition we utilized a lung carcinoma cell line (A549) in which the enzyme was partially silenced and its low activity conformation was stabilized through incubation with 2-deoxyglucose. We measured nucleotide content, reduced glutathione, activities of enzymes involved in glycolysis and Krebs cycle, protein synthesis, mitochondrial function, cellular proliferation, migration and viability. Our results demonstrate that high cN-II expression is associated with a glycolytic, highly proliferating phenotype, while silencing causes a reduction of proliferation, protein synthesis and migration ability, and an increase of oxidative performances. Similar results were obtained in a human astrocytoma cell line. Moreover, we demonstrate that cN-II silencing is concomitant with p53 phosphorylation, suggesting a possible involvement of this pathway in mediating some of cN-II roles in cancer cell biology. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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14 pages, 3479 KiB

Open AccessArticle

Bosutinib Inhibits EGFR Activation in Head and Neck Cancer

by Carmen Segrelles, David Contreras, Elena M. Navarro, Carmen Gutiérrez-Muñoz, Ramón García-Escudero, Jesús M. Paramio and Corina Lorz

Int. J. Mol. Sci. 2018, 19(7), 1824; https://doi.org/10.3390/ijms19071824 - 21 Jun 2018

Cited by 14 | Viewed by 4437

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and although new therapeutic approaches have been recently evaluated, overall patient survival is still poor. Thus, new effective and selective clinical treatments are urgently needed. An analysis of data [...] Read more.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and although new therapeutic approaches have been recently evaluated, overall patient survival is still poor. Thus, new effective and selective clinical treatments are urgently needed. An analysis of data from large-scale, high-throughput drug screening cell line projects identified Bosutinib, a Src/Abl inhibitor that is currently used for the treatment of chronic myelogenous leukemia, as a candidate drug to treat HNSCC. Using a panel of HNSCC-derived cell lines, we found that treatment with Bosutinib reduced cell proliferation and induced apoptosis of sensitive cell lines. The drug rapidly inhibited Src and EGFR (epidermal growth factor receptor) phosphorylation, and sensitivity to Bosutinib was correlated with the activation status of EGFR. Similar findings were observed in in vivo xenograft assays using HNSCC derived cells. Moreover, in the presence of mutations in PIK3CA, the combination of Bosutinib with the PI3Kα inhibitor Alpelisib showed a synergistic effect. These results suggest that Bosutinib could be a new effective drug for the treatment of HNSCC, particularly in tumors with high EGFR activity. Its combination with Alpelisib could especially benefit patients bearing activating mutations of PIK3CA. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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15 pages, 6616 KiB

Open AccessArticle

NSC 95397 Suppresses Proliferation and Induces Apoptosis in Colon Cancer Cells through MKP-1 and the ERK1/2 Pathway

by Navneet Kumar Dubey, Bou-Yue Peng, Chien-Min Lin, Peter D. Wang, Joseph R. Wang, Chun-Hao Chan, Hong-Jian Wei and Win-Ping Deng

Int. J. Mol. Sci. 2018, 19(6), 1625; https://doi.org/10.3390/ijms19061625 - 31 May 2018

Cited by 23 | Viewed by 6848

Abstract

NSC 95397, a quinone-based small molecule compound, has been identified as an inhibitor for dual-specificity phosphatases, including mitogen-activated protein kinase phosphatase-1 (MKP-1). MKP-1 is known to inactivate mitogen-activated protein kinases by dephosphorylating both of their threonine and tyrosine residues. Moreover, owing to their [...] Read more.

NSC 95397, a quinone-based small molecule compound, has been identified as an inhibitor for dual-specificity phosphatases, including mitogen-activated protein kinase phosphatase-1 (MKP-1). MKP-1 is known to inactivate mitogen-activated protein kinases by dephosphorylating both of their threonine and tyrosine residues. Moreover, owing to their participation in tumorigenesis and drug resistance in colon cancer cells, MKP-1 is an attractive therapeutic target for colon cancer treatment. We therefore investigated the inhibitory activity of NSC 95397 against three colon cancer cell lines including SW480, SW620, and DLD-1, and their underlying mechanisms. The results demonstrated that NSC 95397 reduced cell viability and anchorage-independent growth of all the three colon cancer cell lines through inhibited proliferation and induced apoptosis via regulating cell-cycle-related proteins, including p21, cyclin-dependent kinases, and caspases. Besides, by using mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor U0126, we provided mechanistic evidence that the antineoplastic effects of NSC 95397 were achieved via inhibiting MKP-1 activity followed by ERK1/2 phosphorylation. Conclusively, our results indicated that NSC 95397 might serve as an effective therapeutic intervention for colon cancer through regulating MKP-1 and ERK1/2 pathway. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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16 pages, 4514 KiB

Open AccessArticle

Glioma-Associated Oncogene Homolog Inhibitors Have the Potential of Suppressing Cancer Stem Cells of Breast Cancer

by Kuo-Shyang Jeng, Chi-Juei Jeng, I-Shyan Sheen, Szu-Hua Wu, Ssu-Jung Lu, Chih-Hsuan Wang and Chiung-Fang Chang

Int. J. Mol. Sci. 2018, 19(5), 1375; https://doi.org/10.3390/ijms19051375 - 5 May 2018

Cited by 13 | Viewed by 4456

Abstract

Overexpression of Sonic Hedgehog signaling (Shh) pathway molecules is associated with invasiveness and recurrence in breast carcinoma. Therefore, inhibition of the Shh pathway downstream molecule Glioma-associated Oncogene Homolog (Gli) was investigated for its ability to reduce progression and invasiveness of patient-derived breast cancer [...] Read more.

Overexpression of Sonic Hedgehog signaling (Shh) pathway molecules is associated with invasiveness and recurrence in breast carcinoma. Therefore, inhibition of the Shh pathway downstream molecule Glioma-associated Oncogene Homolog (Gli) was investigated for its ability to reduce progression and invasiveness of patient-derived breast cancer cells and cell lines. Human primary breast cancer T2 cells with high expression of Shh signaling pathway molecules were compared with breast cancer line MDA-MB-231 cells. The therapeutic effects of Gli inhibitors were examined in terms of the cell proliferation, apoptosis, cancer stem cells, cell migration and gene expression. Blockade of the Shh signaling pathway could reduce cell proliferation and migration only in MDA-MB-231 cells. Hh pathway inhibitor-1 (HPI-1) increased the percentages of late apoptotic cells in MDA-MB-231 cells and early apoptotic cells in T2 cells. It reduced Bcl2 expression for cell proliferation and increased Bim expression for apoptosis. In addition, Gli inhibitor HPI-1 decreased significantly the percentages of cancer stem cells in T2 cells. HPI-1 worked more effectively than GANT-58 against breast carcinoma cells. In conclusion, HPI-1 could inhibit cell proliferation, reduce cell invasion and decrease cancer stem cell population in breast cancer cells. To target Gli-1 could be a potential strategy to suppress breast cancer stem cells. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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18 pages, 4151 KiB

Open AccessArticle

Luteolin Inhibits Tumorigenesis and Induces Apoptosis of Non-Small Cell Lung Cancer Cells via Regulation of MicroRNA-34a-5p

by Ze-Qun Jiang, Mu-Han Li, Yue-Mu Qin, Hai-Ying Jiang, Xu Zhang and Mian-Hua Wu

Int. J. Mol. Sci. 2018, 19(2), 447; https://doi.org/10.3390/ijms19020447 - 2 Feb 2018

Cited by 98 | Viewed by 6571

Abstract

Luteolin (LTL) exerts remarkable tumor suppressive activity on various types of cancers, including non-small cell lung cancer (NSCLC). However, it is not completely understood whether the mechanism of its action against NSCLC is related to microRNAs (miRNAs). In the present study, we investigated [...] Read more.

Luteolin (LTL) exerts remarkable tumor suppressive activity on various types of cancers, including non-small cell lung cancer (NSCLC). However, it is not completely understood whether the mechanism of its action against NSCLC is related to microRNAs (miRNAs). In the present study, we investigated the anti-tumor effects of LTL on NSCLC in vitro and in vivo. The results revealed that LTL could inhibit cell proliferation and induce apoptosis in both A549 and H460 cells. In a H460 xenograft tumor model of nude mice, LTL significantly suppressed tumor growth, inhibited cell proliferation, and induced apoptosis. miRNA microarray and quantitative PCR (qPCR) analysis indicated that miR-34a-5p was dramatically upregulated upon LTL treatment in tumor tissues. Furthermore, MDM4 was proved to be a direct target of miR-34a-5p by luciferase reporter gene assay. LTL treatment was associated with increased p53 and p21 protein expressions and decreased MDM4 protein expression in both NSCLC cells and tumor tissues. When miR-34a-5p was inhibited in vitro, the protein expressions of Bcl-2 and MDM4 were recovered, while that of p53, p21, and Bax were attenuated. Moreover, caspase-3 and caspase-9 activation induced by LHL treatment in vitro were also suppressed by miR-34a-5p inhibition. Overall, LTL could inhibit tumorigenesis and induce apoptosis of NSCLC cells by upregulation of miR-34a-5p via targeting MDM4. These findings provide novel insight into the molecular functions of LTL that suggest its potential as a therapeutic agent for human NSCLC. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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Review

Jump to: Research

15 pages, 488 KiB

Open AccessReview

Alterations of Signaling Pathways Related to the Immune System in Breast Cancer: New Perspectives in Patient Management

by Andrea Nicolini, Paola Ferrari, Lucrezia Diodati and Angelo Carpi

Int. J. Mol. Sci. 2018, 19(9), 2733; https://doi.org/10.3390/ijms19092733 - 12 Sep 2018

Cited by 12 | Viewed by 4243

Abstract

In recent years, immune manipulation for cancer treatment, including breast cancer, has been increasingly gaining consent, and many attempts have been made, mainly by either strengthening the immune response (IR) or by inhibiting immune evasion. Therefore, elucidating the related mechanisms is of importance [...] Read more.

In recent years, immune manipulation for cancer treatment, including breast cancer, has been increasingly gaining consent, and many attempts have been made, mainly by either strengthening the immune response (IR) or by inhibiting immune evasion. Therefore, elucidating the related mechanisms is of importance due to the potential to improve the management of cancer patients by immunotherapy. This review article summarized some recent experimental studies, which have discovered novel alterations of signaling pathways related to the immune system in breast cancer. These altered signaling pathways have been grouped according to the general biological mechanism involved: tumor-initiating cells (TICs), cancer stem cells (CSCs), immune evasion, tumor growth and progression, prediction of clinical outcome and prediction of response, or resistance to chemotherapy. These altered pathways related to the immune system open clinical opportunities for the prognosis or treatment of patients. Many of these pathways are related to the origin of breast cancer and immune evasion. We recommended development of new drugs which act on these molecular pathways, and the designing of clinical trials to be carried out mainly in breast cancer patients who required adjuvant treatment. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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21 pages, 1578 KiB

Open AccessReview

Magnolol: A Neolignan from the Magnolia Family for the Prevention and Treatment of Cancer

by Abhishek Manoj Ranaware, Kishore Banik, Vishwas Deshpande, Ganesan Padmavathi, Nand Kishor Roy, Gautam Sethi, Lu Fan, Alan Prem Kumar and Ajaikumar B. Kunnumakkara

Int. J. Mol. Sci. 2018, 19(8), 2362; https://doi.org/10.3390/ijms19082362 - 10 Aug 2018

Cited by 139 | Viewed by 10136

Abstract

The past few decades have witnessed widespread research to challenge carcinogenesis; however, it remains one of the most important health concerns with the worst prognosis and diagnosis. Increasing lines of evidence clearly show that the rate of cancer incidence will increase in future [...] Read more.

The past few decades have witnessed widespread research to challenge carcinogenesis; however, it remains one of the most important health concerns with the worst prognosis and diagnosis. Increasing lines of evidence clearly show that the rate of cancer incidence will increase in future and will create global havoc, designating it as an epidemic. Conventional chemotherapeutics and treatment with synthetic disciplines are often associated with adverse side effects and development of chemoresistance. Thus, discovering novel economic and patient friendly drugs that are safe and efficacious is warranted. Several natural compounds have proved their potential against this dreadful disease so far. Magnolol is a hydroxylated biphenyl isolated from the root and stem bark of Magnolia tree. Magnolol can efficiently prevent or inhibit the growth of various cancers originating from different organs such as brain, breast, cervical, colon, liver, lung, prostate, skin, etc. Considering these perspectives, the current review primarily focuses on the fascinating role of magnolol against various types of cancers, and the source and chemistry of magnolol and the molecular mechanism underlying the targets of magnolol are discussed. This review proposes magnolol as a suitable candidate that can be appropriately designed and established into a potent anti-cancer drug. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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28 pages, 1118 KiB

Open AccessReview

Crosstalk between Notch, HIF-1α and GPER in Breast Cancer EMT

by Ernestina M. De Francesco, Marcello Maggiolini and Anna Maria Musti

Int. J. Mol. Sci. 2018, 19(7), 2011; https://doi.org/10.3390/ijms19072011 - 10 Jul 2018

Cited by 111 | Viewed by 9981

Abstract

The Notch signaling pathway acts in both physiological and pathological conditions, including embryonic development and tumorigenesis. In cancer progression, diverse mechanisms are involved in Notch-mediated biological responses, including angiogenesis and epithelial-mesenchymal-transition (EMT). During EMT, the activation of cellular programs facilitated by transcriptional repressors [...] Read more.

The Notch signaling pathway acts in both physiological and pathological conditions, including embryonic development and tumorigenesis. In cancer progression, diverse mechanisms are involved in Notch-mediated biological responses, including angiogenesis and epithelial-mesenchymal-transition (EMT). During EMT, the activation of cellular programs facilitated by transcriptional repressors results in epithelial cells losing their differentiated features, like cell–cell adhesion and apical–basal polarity, whereas they gain motility. As it concerns cancer epithelial cells, EMT may be consequent to the evolution of genetic/epigenetic instability, or triggered by factors that can act within the tumor microenvironment. Following a description of the Notch signaling pathway and its major regulatory nodes, we focus on studies that have given insights into the functional interaction between Notch signaling and either hypoxia or estrogen in breast cancer cells, with a particular focus on EMT. Furthermore, we describe the role of hypoxia signaling in breast cancer cells and discuss recent evidence regarding a functional interaction between HIF-1α and GPER in both breast cancer cells and cancer-associated fibroblasts (CAFs). On the basis of these studies, we propose that a functional network between HIF-1α, GPER and Notch may integrate tumor microenvironmental cues to induce robust EMT in cancer cells. Further investigations are required in order to better understand how hypoxia and estrogen signaling may converge on Notch-mediated EMT within the context of the stroma and tumor cells interaction. However, the data discussed here may anticipate the potential benefits of further pharmacological strategies targeting breast cancer progression. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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13 pages, 1639 KiB

Open AccessReview

Scorpins in the DNA Damage Response

by Dario Palmieri, Anna Tessari and Vincenzo Coppola

Int. J. Mol. Sci. 2018, 19(6), 1794; https://doi.org/10.3390/ijms19061794 - 17 Jun 2018

Cited by 10 | Viewed by 5155

Abstract

The DNA Damage Response (DDR) is a complex signaling network that comes into play when cells experience genotoxic stress. Upon DNA damage, cellular signaling pathways are rewired to slow down cell cycle progression and allow recovery. However, when the damage is beyond repair, [...] Read more.

The DNA Damage Response (DDR) is a complex signaling network that comes into play when cells experience genotoxic stress. Upon DNA damage, cellular signaling pathways are rewired to slow down cell cycle progression and allow recovery. However, when the damage is beyond repair, cells activate complex and still not fully understood mechanisms, leading to a complete proliferative arrest or cell death. Several conventional and novel anti-neoplastic treatments rely on causing DNA damage or on the inhibition of the DDR in cancer cells. However, the identification of molecular determinants directing cancer cells toward recovery or death upon DNA damage is still far from complete, and it is object of intense investigation. SPRY-containing RAN binding Proteins (Scorpins) RANBP9 and RANBP10 are evolutionarily conserved and ubiquitously expressed proteins whose biological functions are still debated. RANBP9 has been previously implicated in cell proliferation, survival, apoptosis and migration. Recent studies also showed that RANBP9 is involved in the Ataxia Telangiectasia Mutated (ATM) signaling upon DNA damage. Accordingly, cells lacking RANBP9 show increased sensitivity to genotoxic treatment. Although there is no published evidence, extensive protein similarities suggest that RANBP10 might have partially overlapping functions with RANBP9. Like RANBP9, RANBP10 bears sites putative target of PIK-kinases and high throughput studies found RANBP10 to be phosphorylated following genotoxic stress. Therefore, this second Scorpin might be another overlooked player of the DDR alone or in combination with RANBP9. This review focuses on the relatively unknown role played by RANBP9 and RANBP10 in responding to genotoxic stress. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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15 pages, 275 KiB

Open AccessReview

Signaling Crosstalk of TGF-β/ALK5 and PAR2/PAR1: A Complex Regulatory Network Controlling Fibrosis and Cancer

by Hendrik Ungefroren, Frank Gieseler, Roland Kaufmann, Utz Settmacher, Hendrik Lehnert and Bernhard H. Rauch

Int. J. Mol. Sci. 2018, 19(6), 1568; https://doi.org/10.3390/ijms19061568 - 24 May 2018

Cited by 40 | Viewed by 7850

Abstract

Both signaling by transforming growth factor-β (TGF-β) and agonists of the G Protein-coupled receptors proteinase-activated receptor-1 (PAR1) and -2 (PAR2) have been linked to tissue fibrosis and cancer. Intriguingly, TGF-β and PAR signaling either converge on the regulation of certain matrix genes overexpressed [...] Read more.

Both signaling by transforming growth factor-β (TGF-β) and agonists of the G Protein-coupled receptors proteinase-activated receptor-1 (PAR1) and -2 (PAR2) have been linked to tissue fibrosis and cancer. Intriguingly, TGF-β and PAR signaling either converge on the regulation of certain matrix genes overexpressed in these pathologies or display mutual regulation of their signaling components, which is mediated in part through sphingosine kinases and sphingosine-1-phosphate and indicative of an intimate signaling crosstalk between the two pathways. In the first part of this review, we summarize the various regulatory interactions that have been discovered so far according to the organ/tissue in which they were described. In the second part, we highlight the types of signaling crosstalk between TGF-β on the one hand and PAR2/PAR1 on the other hand. Both ligand–receptor systems interact at various levels and by several mechanisms including mutual regulation of ligand–ligand, ligand–receptor, and receptor–receptor at the transcriptional, post-transcriptional, and receptor transactivation levels. These mutual interactions between PAR2/PAR1 and TGF-β signaling components eventually result in feed-forward loops/vicious cycles of matrix deposition and malignant traits that exacerbate fibrosis and oncogenesis, respectively. Given the crucial role of PAR2 and PAR1 in controlling TGF-β receptor activation, signaling, TGF-β synthesis and bioactivation, combining PAR inhibitors with TGF-β blocking agents may turn out to be more efficient than targeting TGF-β alone in alleviating unwanted TGF-β-dependent responses but retaining the beneficial ones. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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18 pages, 965 KiB

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Resistance to Anti-Angiogenic Therapy in Cancer—Alterations to Anti-VEGF Pathway

by Yoshiro Itatani, Kenji Kawada, Takamasa Yamamoto and Yoshiharu Sakai

Int. J. Mol. Sci. 2018, 19(4), 1232; https://doi.org/10.3390/ijms19041232 - 18 Apr 2018

Cited by 238 | Viewed by 18021

Abstract

Anti-angiogenic therapy is one of the promising strategies for many types of solid cancers. Bevacizumab (Avastin), a recombinant humanized monoclonal antibody of vascular endothelial growth factor (VEGF) A, was approved for the first time as an anti-angiogenic drug for the treatment of metastatic [...] Read more.

Anti-angiogenic therapy is one of the promising strategies for many types of solid cancers. Bevacizumab (Avastin), a recombinant humanized monoclonal antibody of vascular endothelial growth factor (VEGF) A, was approved for the first time as an anti-angiogenic drug for the treatment of metastatic colorectal cancer (CRC) by the Food and Drug Administration (FDA) in 2004. In addition, the other VEGF pathway inhibitors including small molecule tyrosine kinase inhibitors (sunitinib, sorafenib, and pazopanib), a soluble VEGF decoy receptor (aflibercept), and a humanized monoclonal antibody of VEGF receptor 2 (VEGFR2) (ramucirumab) have been approved for cancer therapy. Although many types of VEGF pathway inhibitors can improve survival in most cancer patients, some patients have little or no beneficial effect from them. The primary or acquired resistance towards many oncological drugs, including anti-VEGF inhibitors, is a common problem in cancer treatment. This review summarizes the proposed alternative mechanisms of angiogenesis other than the VEGF pathway. These mechanisms are involved in the development of resistance to anti-VEGF therapies in cancer patients. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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