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Cell Signal. 2017 Dec;40:172-182. doi: 10.1016/j.cellsig.2017.09.006. Epub 2017 Sep 18.

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).

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


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.


AEG-1; AMPK; Autophagy; C42B; LNCaP; Prostate cancer

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