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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-dependent kinase (AMPK)

Title:

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-dependent kinase (AMPK)

Draz, Hossam, Goldberg, Alexander A., Titorenko, Vladimir I. ORCID: https://orcid.org/0000-0001-5819-7545, Guns, Emma, Safe, Stephen H. and Sanderson, J. Thomas (2017) 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-dependent kinase (AMPK). Cellular Signalling . ISSN 08986568 (In Press)

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Official URL: http://dx.doi.org/10.1016/j.cellsig.2017.09.006

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 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 AMP-activated protein kinase (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.

Divisions:Concordia University > Faculty of Arts and Science > Biology
Item Type:Article
Refereed:Yes
Authors:Draz, Hossam and Goldberg, Alexander A. and Titorenko, Vladimir I. and Guns, Emma and Safe, Stephen H. and Sanderson, J. Thomas
Journal or Publication:Cellular Signalling
Date:18 September 2017
Funders:
  • Canadian Institutes of Health Research (CIHR grant no. MOP-115019)
  • Fonds de Recherche du Québec - Santé (FRQS)
Digital Object Identifier (DOI):10.1016/j.cellsig.2017.09.006
Keywords:Prostate cancer; LNCaP; C42B; Autophagy; AMPK; AEG-1
ID Code:983075
Deposited By: DANIELLE DENNIE
Deposited On:22 Sep 2017 13:18
Last Modified:28 May 2019 19:08

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