MicroRNA-337-3p suppresses cell viability, apoptosis, and autophagy by modulating PPARγ expression in androgen-dependent human prostate cancer

Hao Wang,Hanfeng Xu,Youjun Duan,Libo Chen

doi:10.1080/26895293.2020.1736188

Hao Wang, Hanfeng Xu + Show 2 more

Open Access

https://doi.org/10.1080/26895293.2020.1736188

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Abstract

We proposed that autophagy activated through PPARγ in prostate cancer could protect cancer against androgen deprivation. Our MTT and western blotting assay results showed that mimics of miR-337-3p repressed autophagy flux under androgen deprivation, whereas inhibitors had the opposite effect. Neither mimics nor inhibitors influenced cell motility and invasion. miR-337-3p downregulated PPARγ expression in dual luciferase reporter assays and promoted AMPK phosphorylation. The overexpression of PPARγ or AMPK agonists partly diminished the adverse influence of mimics on proliferation and cell autophagy. In a mouse xenograft model, tumors transplanted with LNCap cells having a miR-337-3p deficiency had a significantly larger volume and lower rate of apoptosis than in controls after orchidectomy. Our findings showed that the negative effects of miR-337-3p on cell survival after androgen deprivation through PPARγ degeneration and modulated autophagy could serve as a novel therapeutic target for androgen-dependent prostate cancer and provide a strategy against resistance to anti-androgen therapy.

Highlights

Autophagy is the removal of damaged organelles by cell degradation and recycling; it is a cell survival mechanism that could promote the progression of prostate cancer (PCa) (Farrow et al 2014; Blessing et al 2017)
Our findings showed that the negative effects of miR-337-3p on cell survival after androgen deprivation through PPARγ degeneration and modulated autophagy could serve as a novel therapeutic target for androgen-dependent prostate cancer and provide a strategy against resistance to anti-androgen therapy
We showed that PPARγ promoted autophagy in PCa cells through AMPK signaling after miR-337-3p inhibition and caused resistance

Summary

Introduction

Autophagy is the removal of damaged organelles by cell degradation and recycling; it is a cell survival mechanism that could promote the progression of prostate cancer (PCa) (Farrow et al 2014; Blessing et al 2017). A study on non-neoplastic diseases showed that telmisartan, a partial agonist of PPARγ and a target of NAD-dependent deacetylase (SIRT1), improved the sensitivity of insulin in obese db/db mice fed with a high-fat diet, decreased the size of hypertrophic pancreatic islets, and increased AMPK phosphorylation. It showed that a relationship between increased AMPK phosphorylation and PPARγ activation in metabolic diseases might lead to the activation of autophagy-dependent upregulation of AMPK signaling (Shiota et al 2012)

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