Gamma secretase inhibitor impairs epithelial-to-mesenchymal transition induced by TGF-β in ovarian tumor cell lines

Pazos, Maria C.; Abramovich, Dalhia; Bechis, Andrés; Accialini, Paula; Parborell, Fernanda; Tesone, Marta; Irusta, Griselda

doi:10.1016/j.mce.2016.11.025

Cited by 24 publications

(28 citation statements)

References 63 publications

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“…Additionally, zinc finger E-box binding homeobox 1 (ZEB1) belonging to zinc finger transcription factor superfamily was found to be involved in regulating transcription ( 14 ). Many studies have reported the function of ZEB1 in the occurrence of human cancers including osteosarcoma and cervical cancer ( 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

miR‑205‑5p inhibits cell migration and invasion in prostatic carcinoma by targeting ZEB1

2018

Oncol Lett

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Many studies have demonstrated that miRNAs have influence on tumorigenesis and progression of human cancers, including invasion and migration. Thus, the role of miR-205/ZEB1 axis for the migration and invasion of prostate cancer cells was explored in the present study. The miR-205-5p and zinc finger E-box binding homeobox 1 (ZEB1) mRNA expression levels were observed in prostate cancer tissues or cell lines via reverse transcription-quantitative PCR (RT-qPCR), and the protein level of ZEB1 was measured by western blotting. Dual-Luciferase Reporter Assay was used to verify the relationship between miR-205-5p and ZEB1. In addition, cell migration and invasion was measured by Transwell assay. The results revealed that, compared with the control, downregulation of miR-205-5p was detected in prostate cancer tissues and cell lines, and miR-205-5p overexpression was found to inhibit cell migration and invasion. Moreover, miR-205-5p was confirmed to directly target ZEB1 in prostate cancer. Importantly, ZEB1 was identified to weaken the inhibitory effect of miR-205-5p in prostate cancer. In conclusion, miR-205-5p inhibited cell migration and invasion in prostatic carcinoma by targeting ZEB1 and miR-205-5p/ZEB1 axis shows potential to be developed in therapeutic strategies for prostate cancer.

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Section: Introductionmentioning

confidence: 99%

miR‑205‑5p inhibits cell migration and invasion in prostatic carcinoma by targeting ZEB1

2018

Oncol Lett

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“…Moreover, in 2011, the Cancer Genome Atlas published a study performed in 316 cases of High Grade Serous Ovarian Cancer, 22% of which showed an alteration in the Notch signaling pathway among other deregulated signaling pathways (The Cancer Genome Atlas Research Network, 2011). In addition, in a granulosa tumor cell line representative of the adult form of Granulosa Cell Tumors, we have previously demonstrated that JAGGED1, DLL4, NOTCH1, and NOTCH4 are highly expressed in tumor cells as compared to that observed in granulosalutein cells obtained from patients undergoing assisted reproductive techniques (Pazos et al, 2017). Notch signaling inhibitors have been developed in recent years, and some are in current clinical trials.…”

Section: Discussionmentioning

confidence: 99%

PDGFB as a vascular normalization agent in an ovarian cancer model treated with a gamma‐secretase inhibitor

Pazos

Sequeira

Bocchicchio

et al. 2018

Journal Cellular Physiology

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Ovarian cancer is the fifth leading cause of cancer-related deaths in women. In the past 20 years, the canonical types of drugs used to treat ovarian cancer have not been replaced and the survival rates have not changed. These facts show the clear need to find new therapeutic strategies for this illness. Thus, the aim of the present study was to investigate the effect of a gamma-secretase inhibitor (DAPT) in combination with the Platelet-derived growth factor B (PDGFB) on an ovarian cancer xenograft model. To achieve this goal, we analyzed the effect of the administration of DAPT alone and the co-administration of DAPT and recombinant PDGFB on parameters associated with tumor growth and angiogenesis in an orthotopic experimental model of ovarian cancer. We observed that the dose of DAPT used was ineffective to reduce ovarian tumor growth, but showed anticancer activity when co-administered with recombinant PDGFB. The administration of PDGFB alone normalized tumor vasculature by increasing periendothelial coverage and vascular functionality. Interestingly, this effect exerted by PDGFB was also observed in the presence of DAPT. Our findings suggest that PDGFB is able to improve tumor vascularity and allows the anticancer action of DAPT in the tumor. We propose that this therapeutic strategy could be a new tool for ovarian cancer treatment and deserves further studies.

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“…Moreover, the effects of Gremlin on wound healing speed were also inhibited by DAPT ( Figure 8 ). DAPT alone did not show effect on wound healing when compared to control ( Pazos et al, 2017 ).…”

Section: Resultsmentioning

confidence: 84%

Gremlin Regulates Tubular Epithelial to Mesenchymal Transition via VEGFR2: Potential Role in Renal Fibrosis

et al. 2018

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Chronic kidney disease (CKD) is emerging as an important health problem due to the increase number of CKD patients and the absence of an effective curative treatment. Gremlin has been proposed as a novel therapeutic target for renal inflammatory diseases, acting via Vascular Endothelial Growth Factor Receptor-2 (VEGFR2). Although many evidences suggest that Gremlin could regulate renal fibrosis, the receptor involved has not been yet clarified. Gremlin, as other TGF-β superfamily members, regulates tubular epithelial to mesenchymal transition (EMT) and, therefore, could contribute to renal fibrosis. In cultured tubular epithelial cells Gremlin binding to VEGFR2 is linked to proinflammatory responses. Now, we have found out that in these cells VEGFR2 is also involved in the profibrotic actions of Gremlin. VEGFR2 blockade by a pharmacological kinase inhibitor or gene silencing diminished Gremlin-mediated gene upregulation of profibrotic factors and restored changes in EMT-related genes. Moreover, VEGFR2 inhibition blocked EMT phenotypic changes and dampened the rate of wound healing in response to Gremlin. The role of VEGFR2 in experimental fibrosis was evaluated in experimental unilateral ureteral obstruction. VEFGR2 inhibition diminished the upregulation of profibrotic genes and EMT changes, as well as the accumulation of extracellular matrix proteins, such as fibronectin and collagens in the obstructed kidneys. Notch pathway activation participates in renal damage progression by regulating cell growth/proliferation, regeneration and inflammation. In cultured tubular epithelial cells, Notch inhibition markedly downregulated Gremlin-induced EMT changes and wound healing speed. These results show that Gremlin regulates the EMT process via VEGFR2 and Notch pathway activation, suggesting that the Gremlin/VEGFR2 axis could be a potential therapeutic target for CKD.

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Gamma secretase inhibitor impairs epithelial-to-mesenchymal transition induced by TGF-β in ovarian tumor cell lines

Cited by 24 publications

References 63 publications

miR‑205‑5p inhibits cell migration and invasion in prostatic carcinoma by targeting ZEB1

miR‑205‑5p inhibits cell migration and invasion in prostatic carcinoma by targeting ZEB1

PDGFB as a vascular normalization agent in an ovarian cancer model treated with a gamma‐secretase inhibitor

Gremlin Regulates Tubular Epithelial to Mesenchymal Transition via VEGFR2: Potential Role in Renal Fibrosis

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