Ring-DIMs induce mitochondrial dysfunction and ER stress in human prostate cancer cells
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AbstractWe have previously shown that a series of brominated and chlorinated analogs of 3,3'-diindolylmethane (DIM) can inhibit can induce apoptosis and necrosis in androgen-dependent and androgen-independent prostate cancer cells and that addition of bromine to the 4 and 4 position of the indole ring of DIM maximally increases the potency of the anticancer compound. To understand the upstream events leading to the activation of caspases in response to treatment with ring-DIMs in androgen-dependent LNCaP and androgen-independent LNCaP C4-2B cells by monitoring the onset of endoplasmic reticulum (ER) stress and the dysregulation of mitochondrial respiration. We found that 4,4'-dibromo- and 7,7'-dichloroDIM and DIM itself induced ER stress-dependent upregulation of CHOP, ATF4, and GRP78, while only 4,4'-dibromo and 7,7'-dichloroDIM induced phosphorylation of eIF2alpha and JNK. Both ER stress and loss of mitochondrial membrane potential were observed after treatment with 4,4'-dihaloDIMs and DIM, but not 7,7'-dihaloDIMs within 1 hour of exposure, before the appearance of later stage apoptotic events such as condensed chromatin. Salubrinal inhibited cell death induced by 4,4'-dihaloDIMs, but facilitated cell death induced by 7,7'-dihaloDIMs or DIM. Interestingly, salubrinal did not increase eIF2alpha phosphorylation after co-treatment with either DIM or ring-DIMs. However, it did restore mitochondrial membrane potential in cells treated with 4,4'dihaloDIMs and further decreased mitochondrial activity after co-treatment with 7,7'-dihaloDIMs or DIM. Moreover, cyclosporin A inhibited cell death induced by both 4,4-dihalo and 7,7-dihaloDIMs but not DIM. Taken together, these data suggest that the ring-DIMs induce cell death via mitochondrial dysfunction and ER stress, and that because salubrinal either stimulates or inhibits cell death in combination with specific ring-DIMs, its effects are related to mitochondrial membrane integrity and not to phosphorylation of eIF2alpha.Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B256.Citation Format: Alexander A. Goldberg, Diana Montes-Grajales, Jesus Olivero, Adam Beach, Vladimir Titorenko, Steven Safe, Thomas Sanderson. Ring-DIMs induce mitochondrial dysfunction and ER stress in human prostate cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B256.
