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Diindolylmethane and its halogenated derivatives induce protective autophagy in human prostate cancer cells via induction of astrocyte elevated gene-1 (AEG-1) and activation of AMP-dependent kinase (AMPK).

Draz, Hossam; Goldberg, Mark S; Safe, Stephen; Sanderson, J. Thomas (2016). Diindolylmethane and its halogenated derivatives induce protective autophagy in human prostate cancer cells via induction of astrocyte elevated gene-1 (AEG-1) and activation of AMP-dependent kinase (AMPK). In: 12ème colloque du centre de recherche Biomed, 5 mai 2016, Centre de congrès Palace, Laval (Québec).

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Résumé

We have previously shown that 3,3'-diindolylmethane (DIM) and its halogenated derivatives (ring-DIMs) induce apoptosis and autophagy in human prostate cancer cells. The mechanisms of action of ring-DIMs are not fully understood, but are multifaceted and dependent on halogen substitution pattern. As DIM is an ATPase inhibitor, we hypothesized that DIM and ring-DIMs induce autophagy via activation of AMPK in prostate cancer cells. Autophagic activity was monitored by GFP-LC3B punctuation and LC3B-I to LC3B-II conversion in LNCaP and C42B prostate cancer cells. Mitochondrial proteomic analysis was done by LC-MS/MS. Protein levels for AMPK, pAMPK, acetyl-CoA carboxylase (ACC), pACC , AEG-1, pULK-1 and β-actin were measured by western blot. AMPK and AEG-1 gene expression was downregulated using siRNA. Apoptosis and necrosis were assessed with Hoechst 33342 and propidium iodide, respectively. DIM and ring-DIMs induced autophagy by increasing LC3BI to LC3BII conversion and LC3B punctuation in LNCaP and C42B cells. DIM and ring-DIMs induced AMPK, ULK-1 and ACC phosphorylation concentration-and time-dependently. Interestingly, DIM, 4,4' dibromoDIM and 7,7' dichloroDIM induced the oncogenic protein AEG-1. LC-MS/MS analysis revealed that AEG-1 was recruited to the mitochondria upon ring-DIM treatment. Downregulation of AEG-1 or AMPK significantly inhibited DIM-or ringDIM-induced autophagy. Pretreatment with autophagy inhibitors baflomycin, 3-methyladenine, the ULK1 inhibitor MRT 67307 or siRNAs targeting AEG-1 or AMPK significantly exacerbated the cytotoxicity of DIM and ring-DIMs. In summary, we identified a novel mechanism for DIM-and ring-DIM-induced protective autophagy, via induction of AEG-1 and activation of AMPK. Our findings could help towards the development of novel drug therapies for prostate cancer that include selective autophagy inhibitors as adjuvants. Diindolylmethane and its halogenated derivatives induce protective autophagy in human prostate cancer cells via induction of astrocyte elevated gene-1 (AEG-1) and activation of AMP-dependent kinase (AMPK).

Type de document: Document issu d'une conférence ou d'un atelier
Mots-clés libres: 3,3’-diindolylmethane, prostate cancer cells, AMPK, AEG-1, autophagy
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 24 déc. 2017 17:42
Dernière modification: 24 déc. 2017 17:42
URI: http://espace.inrs.ca/id/eprint/5821

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