Lithocholic acid induces endoplasmic reticulum stress, autophagy and mitochondrial dysfunction in human prostate cancer cells

PeerJ

article

Ahmed A. Gafar¹  Hossam M. Draz¹  Alexander A. Goldberg¹  Mohamed A. Bashandy²  Sayed Bakry²  Mahmoud A. Khalifa²  Walid AbuShair²  Vladimir I. Titorenko⁵  J. Thomas Sanderson¹ 

[1] Institut Armand-Frappier, Institut National de la Recherche Scientifique;Zoology Department, Faculty of Science, Al-Azhar University;Department of Biochemistry, National Research Centre;McGill University Health Centre;Department of Biology, Concordia University

关键词: Lithocholic acid;    Prostate cancer cells;    Pc-3;    Du-145;    Autophagy;    Endoplasmic reticulum stress;    RWPE-1;    Cell death;    Reactive oxygen species;    Tocotrienol;   

DOI  :  10.7717/peerj.2445

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

Lithocholic acid (LCA) is a secondary bile acid that is selectively toxic to human neuroblastoma, breast and prostate cancer cells, whilst sparing normal cells. We previously reported that LCA inhibited cell viability and proliferation and induced apoptosis and necrosis of androgen-dependent LNCaP and androgen-independent PC-3 human prostate cancer cells. In the present study, we investigated the roles of endoplasmic reticulum (ER) stress, autophagy and mitochondrial dysfunction in the toxicity of LCA in PC-3 and autophagy deficient, androgen-independent DU-145 cells. LCA induced ER stress-related proteins, such as CCAAT-enhancer-binding protein homologous protein (CHOP), and the phosphorylation of eukaryotic initiation factor 2-alpha (p-eIF2α10 µM) increased levels of reactive oxygen species (ROS) concentration-dependently in PC-3 cells, whereas ROS levels were not affected in DU-145 cells. Salubrinal, an inhibitor of eIF2α dephosphorylation and ER stress, reduced LCA-induced CHOP levels slightly in PC-3, but not DU-145 cells. Salubrinal pre-treatment increased the cytotoxicity of LCA in PC-3 and DU-145 cells and resulted in a statistically significant loss of cell viability at normally non-toxic concentrations of LCA. The late-stage autophagy inhibitor bafilomycin A1 exacerbated LCA toxicity at subtoxic LCA concentrations in PC-3 cells. The antioxidant α-tocotrienol strongly inhibited the toxicity of LCA in PC-3 cells, but not in DU-145 cells. Collectively, although LCA induces autophagy and ER stress in PC-3 cells, these processes appear to be initially of protective nature and subsequently consequential to, but not critical for the ROS-mediated mitochondrial dysfunction and cytotoxicity of LCA. The full mechanism of LCA-induced mitochondrial dysfunction and cytotoxicity in the similarly sensitive DU-145 cells remains to be elucidated.

【 授权许可】

CC BY