Resveratrol activates autophagic cell death in prostate cancer cells via downregulation of STIM1 and the mTOR pathway

Senthil Selvaraj, Yuyang Sun, Pramod Sukumaran, Brij B. Singh

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Resveratrol (RSV), a natural polyphenol, has been suggested to induce cell cycle arrest and activate apoptosis-mediated cell death in several cancer cells, including prostate cancer. However, several molecular mechanisms have been proposed on its chemopreventive action, the precise mechanisms by which RSV exerts its anti-proliferative effect in androgen-independent prostate cancer cells remain questionable. In the present study, we show that RSV activates autophagic cell death in PC3 and DU145 cells, which was dependent on stromal interaction molecule 1 (STIM1) expression. RSV treatment decreases STIM1 expression in a time-dependent manner and attenuates STIM1 association with TRPC1 and Orai1. Furthermore, RSV treatment also decreases ER calcium storage and store operated calcium entry (SOCE), which induces endoplasmic reticulum (ER) stress, thereby, activating AMPK and inhibiting the AKT/mTOR pathway. Similarly, inhibition of SOCE by SKF-96365 decreases the survival and proliferation of PC3 and DU145 cells and inhibits AKT/mTOR pathway and induces autophagic cell death. Importantly, SOCE inhibition and subsequent autophagic cell death caused by RSV was reversed by STIM1 overexpression. STIM1 overexpression restored SOCE, prevents the loss of mTOR phosphorylation and decreased the expression of CHOP and LC3A in PC3 cells. Taken together, for the first time, our results revealed that RSV induces autophagy-mediated cell death in PC3 and DU145 cells through regulation of SOCE mechanisms, including downregulating STIM1 expression and trigger ER stress by depleting ER calcium pool.

Original languageEnglish
JournalMolecular Carcinogenesis
DOIs
Publication statusAccepted/In press - 2015

Fingerprint

Autophagy
Prostatic Neoplasms
Down-Regulation
Calcium
1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole
Endoplasmic Reticulum Stress
Endoplasmic Reticulum
Cell Death
AMP-Activated Protein Kinases
Polyphenols
Cell Cycle Checkpoints
resveratrol
Stromal Interaction Molecule 1
Androgens
Phosphorylation
Apoptosis
Neoplasms

Keywords

  • Autophagy
  • ER stress
  • Orai1
  • Prostate cancer
  • Resveratrol
  • SOCE
  • STIM1
  • TRPC1

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

Resveratrol activates autophagic cell death in prostate cancer cells via downregulation of STIM1 and the mTOR pathway. / Selvaraj, Senthil; Sun, Yuyang; Sukumaran, Pramod; Singh, Brij B.

In: Molecular Carcinogenesis, 2015.

Research output: Contribution to journalArticle

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