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)
| Autor: | Hossam M. Draz, Alexander A. Goldberg, J. Thomas Sanderson, Stephen Safe, Vladimir I. Titorenko, Emma S. Tomlinson Guns |
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| Přispěvatelé: | National Research Centre - NRC (EGYPT), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), McGill University = Université McGill [Montréal, Canada], Concordia University [Montreal], University of British Columbia (UBC), Texas A&M University [College Station], This work was funded by an operating grant from the Canadian Institutes of Health Research (CIHR grant no. MOP-115019) to JTS, EG and SS. HD received a scholarship from the Fonds de Recherche du Québec - Santé (FRQS). All authors declare to have no conflicts of interest. |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine AMPK MESH: Signal Transduction Indoles Halogenation genetic structures Carcinogenesis [SDV]Life Sciences [q-bio] Apoptosis AMP-Activated Protein Kinases 0302 clinical medicine AMP-activated protein kinase MESH: RNA Small Interfering MESH: AMP-Activated Protein Kinases RNA Small Interfering MESH: Indoles Prostate cancer biology Chemistry LNCaP RNA-Binding Proteins MESH: Carcinogenesis 3. Good health Cell biology 030220 oncology & carcinogenesis MESH: Cell Adhesion Molecules AEG-1 Signal Transduction Atg1 MESH: Cell Line Tumor Diindolylmethane 03 medical and health sciences Cell Line Tumor Autophagy Humans MESH: Autophagy C42B Protein kinase A MESH: Halogenation MESH: Humans MESH: Apoptosis Membrane Proteins Prostatic Neoplasms Cell Biology MESH: Male 030104 developmental biology MESH: Prostatic Neoplasms Cancer cell biology.protein sense organs Cell Adhesion Molecules |
| Zdroj: | Cellular Signalling Cellular Signalling, Elsevier, 2017, 40, pp.172-182. ⟨10.1016/j.cellsig.2017.09.006⟩ |
| ISSN: | 0898-6568 |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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