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Nintedanib inhibits growth of human prostate carcinoma cells by modulating both cell cycle and angiogenesis regulators.

ABSTRACT: Prostate cancer (PCa) is the most common malignancy and second leading cause of cancer-related deaths in American men. Proliferating cells have higher need for nutrients and oxygen, triggering angiogenesis that plays a critical role in tumor growth, progression and metastasis. Consequently, immense focus has converged onto inhibitors of angiogenesis in cancer treatment, such as Nintedanib, which has shown exceptional antitumor activity via inhibiting cell proliferation and the resulting tumor growth, primarily due to its combined action on tumor cells, endothelial cells and pericytes. Accordingly, here we assessed both in vitro and in vivo efficacy of Nintedanib in PCa. The results showed that Nintedanib decreased cell viability in both androgen dependent- and -independent PCa cells, together with a decrease in cell motility and invasiveness. Nintedanib also reduced the expression of significant genes responsible for cell cycle progression. PCa PC3 xenograft-carrying nude mice treated with Nintedanib showed significantly decreased tumor volume and cell proliferation alongside diminished levels of pro-angiogenic molecules and blood vessel densities. In conclusion, we report that Nintedanib has strong efficacy against PCa in pre-clinical models via modulation of various pathways, and that it could be employed as a promising new strategy to manage PCa clinically.

SUBMITTER: da Silva RF

PROVIDER: S-EPMC6014981 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Nintedanib inhibits growth of human prostate carcinoma cells by modulating both cell cycle and angiogenesis regulators.

da Silva Raquel Frenedoso RF Dhar Deepanshi D Raina Komal K Kumar Dileep D Kant Rama R Cagnon Valeria Helena Alves VHA Agarwal Chapla C Agarwal Rajesh R

Scientific reports 20180622 1

Prostate cancer (PCa) is the most common malignancy and second leading cause of cancer-related deaths in American men. Proliferating cells have higher need for nutrients and oxygen, triggering angiogenesis that plays a critical role in tumor growth, progression and metastasis. Consequently, immense focus has converged onto inhibitors of angiogenesis in cancer treatment, such as Nintedanib, which has shown exceptional antitumor activity via inhibiting cell proliferation and the resulting tumor gr ...[more]

PMID: 29934570

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Project description:BackgroundAngiogenesis plays critical roles in the progression and metastasis of malignant tumors. Gastric neuroendocrine carcinoma is an uncommon stomach cancer that is rich in blood vessels and exhibits highly malignant biological behavior with a poor prognosis. The role of CDK5RAP3 in GNEC has not been reported to date.MethodsImmunohistochemistry was used to assess the expression of CDK5RAP3 in GNEC tissues and adjacent non-tumor tissues. Cell lines with stable overexpression or knockdown of CDK5RAP3 were constructed using lentiviral transfection. Wound-healing assays, invasion and metastasis assays, tube formation assays, and tumor xenograft transplantation assays were performed to evaluate the effect of CDK5RAP3 on GNEC angiogenesis in vitro and in vivo. Real-time PCR, ELISA, western blot analysis, and confocal-immunofluorescence staining were used to explore the molecular mechanism of CDK5RAP3's effect on angiogenesis.ResultsCompared with their respective adjacent non-tumor tissues, protein levels of CDK5RAP3 were significantly decreased in GNEC tissues. Furthermore, low expression of CDK5RAP3 was correlated with more advanced TNM stage, increased tumor microvessel density, and poor prognosis. Functionally, we found that GNEC cells with CDK5RAP3 knockdown promoted human umbilical vein endothelial cells migration and tube formation via activation of AKT/HIF-1α/VEGFA signaling, resulting in increased levels of VEGFA in GNEC cell supernatant. In addition, CDK5RAP3 overexpression in GNEC cells caused the opposing effect. Consistent with these results, nude mouse tumorigenicity assays showed that CDK5RAP3 expression downregulated angiogenesis in vivo. Lastly, patients with low CDK5RAP3 expression and high VEGFA expression exhibited the worst prognosis.ConclusionsThis study demonstrated that CDK5RAP3 inhibits angiogenesis by downregulating AKT/HIF-1α/VEGFA signaling in GNEC and improves patient prognosis, suggesting that CDK5RAP3 could be a potential therapeutic target for GNEC.

Dataset Information

Nintedanib inhibits growth of human prostate carcinoma cells by modulating both cell cycle and angiogenesis regulators.

Publications

Nintedanib inhibits growth of human prostate carcinoma cells by modulating both cell cycle and angiogenesis regulators.

Similar Datasets

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