1 INRS-Institut Armand-Frappier, Laval, QC, Canada; Department of Biochemistry, National Research Centre, Dokki, Cairo, Egypt.
2 INRS-Institut Armand-Frappier, Laval, QC, Canada; Critical Care Division and Meakins-Christie Laboratories, Faculty of Medicine, McGill University, Montréal, QC, Canada.
3 Department of Biology, Concordia University, Montréal, QC, Canada.
4 The Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
5 Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, United States.
6 INRS-Institut Armand-Frappier, Laval, QC, Canada. Electronic address: thomas.sanderson@iaf.inrs.ca.

Diindolylmethane and its halogenated derivatives induce protective autophagy in human prostate cancer cells via induction of the oncogenic protein AEG-1 and activation of AMP-activated protein kinase (AMPK).

Cell Signal. 2017 12;40:172-182

Authors: Draz H, Goldberg AA, Titorenko VI, Tomlinson Guns ES, Safe SH, Sanderson JT

Abstract

3,3'-Diindolylmethane (DIM) and its synthetic halogenated derivatives 4,4'-Br2- and 7,7'-Cl2DIM (ring-DIMs) have recently been shown to induce protective autophagy in human prostate cancer cells. The mechanisms by which DIM and ring-DIMs induce autophagy have not been elucidated. As DIM is a mitochondrial ATP-synthase inhibitor, we hypothesized that DIM and ring-DIMs induce autophagy via alteration of intracellular AMP/ATP ratios and activation of AMP-activated protein kinase (AMPK) signaling in prostate cancer cells. We found that DIM and ring-DIMs induced autophagy was accompanied by increased autophagic vacuole formation and conversion of LC3BI to LC3BII in LNCaP and C42B human prostate cancer cells. DIM and ring-DIMs also induced AMPK, ULK-1 (unc-51-like autophagy activating kinase 1; Atg1) and acetyl-CoA carboxylase (ACC) phosphorylation in a time-dependent manner. DIM and the ring-DIMs time-dependently induced the oncogenic protein astrocyte-elevated gene 1 (AEG-1) in LNCaP and C42B cells. Downregulation of AEG-1 or AMPK inhibited DIM- and ring-DIM-induced autophagy. Pretreatment with ULK1 inhibitor MRT 67307 or siRNAs targeting either AEG-1 or AMPK potentiated the cytotoxicity of DIM and ring-DIMs. Interestingly, downregulation of AEG-1 induced senescence in cells treated with overtly cytotoxic concentrations of DIM or ring-DIMs and inhibited the onset of apoptosis in response to these compounds. In summary, we have identified a novel mechanism for DIM- and ring-DIM-induced protective autophagy, via induction of AEG-1 and subsequent activation of AMPK. Our findings could facilitate the development of novel drug therapies for prostate cancer that include selective autophagy inhibitors as adjuvants.

PMID: 28923415 [PubMed - indexed for MEDLINE]