Abstract 3298: Diindolylmethane and its halogenated analogues induce autophagy in human prostate cancer cells via induction of the astrocyte-elevated gene-1 (AEG-1)
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Abstract3,3-diindolylmethane (DIM) and its halogenated derivatives (ring-DIMs) are recently shown to induce protective autophagy in human prostate cancer cells. The mechanism of induction of autophagy by DIM has not been elucidated. As DIM is a mitochondrial ATP synthase inhibitor, we hypothesized that DIM and ring-DIMs induce autophagy via alteration of AMP/ATP ratio and activation of AMPK signaling in prostate cancer cells. Autophagic activity was monitored by LC3B-I to LC3B-II conversion in LNCaP and C42B prostate cancer cells. Autophagic vacuoles were examined using Cyto-ID autophagy detection kit and transmission electron microscope (TEM). Protein levels for AMPK, pAMPK, acetyl-CoA carboxylase (ACC), pACC, AEG-1, pULK-1 and -actin were measured by western blot. AMPK and AEG-1 gene expression was downregulated using siRNA. DIM and ring-DIMs induced autophagy by increasing autophagic vacuoles and LC3B-I to LC3B-II conversion in LNCaP and C42B cells. These compounds also induced AMPK, ULK-1 and ACC phosphorylation in a time dependent manner. Interestingly, DIM, 4,4 dibromoDIM and 7,7 dichloroDIM induced the oncogenic protein AEG-1 time dependently 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 AEG-1 or AMPK potentiated the cytotoxicity of DIM and ring-DIMs. Interestingly, downregulation of AEG-1 induced senescence in cells treated with toxic concentrations of DIM or ring-DIMs, and inhibited the onset of apoptosis in response to DIM or 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.Citation Format: Hossam Draz, Alexander Goldberg, Thomas Sanderson, Stephen Safe. Diindolylmethane and its halogenated analogues induce autophagy in human prostate cancer cells via induction of the astrocyte-elevated gene-1 (AEG-1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3298. doi:10.1158/1538-7445.AM2017-3298
