title: Autophagy induction by capsaicin in malignant human breast cells is modulated by p38 and extracellular signal-regulated mitogen-activated protein kinases and retards cell death by suppressing endoplasmic reticulum stress-mediated apoptosis.
abstract: In our previous study, we showed that capsaicin induces autophagy in several cell lines. Here, we investigated the molecular mechanisms of capsaicin-induced autophagy in malignant (MCF-7 and MDA-MB-231) and normal (MCF10A) human breast cells. Capsaicin caused nonapoptotic cell cycle arrest of MCF-7 and MDA-MB-231 cells but induced apoptosis in MCF10A cells. In MCF-7 and MDA-MB-231 cells, capsaicin induced endoplasmic reticulum (ER) stress via inositol-requiring 1 and Chop and induced autophagy, as demonstrated by microtubule-associated protein 1 light chain-3 (LC3) conversion. Autophagy blocking by 3-methyladenine (3MA) or bafilomycin A1 (BaF1) activated caspase-4 and -7 and enhanced cell death. In MCF-7 and MDA-MB-231 cells, p38 was activated for more than 48 h by capsaicin treatment, but extracellular signal-regulated kinase (ERK) activation decreased after 12 h, and LC3II levels continuously increased. Furthermore, treatment with 3MA markedly down-regulated capsaicin-induced p38 activation and LC3 conversion, and BaF1 completely down-regulated ERK activation and led to LC3II accumulation. In addition, pharmacological blockade or knockdown of the p38 gene down-regulated Akt activation and LC3II levels but did not affect ERK, and pharmacological blockade or knockdown of the ERK gene up-regulated LC3II induction by capsaicin. Knockdown of inositol-requiring 1 down-regulated p38-Akt signaling. In MCF10A cells, capsaicin did not elicit p38 activation and LC3 conversion and caused the sustained activation of caspase-4. Collectively, capsaicin-induced autophagy is regulated by p38 and ERK; p38 controls autophagy at the sequestration step, whereas ERK controls autophagy at the maturation step, and that autophagy is involved in the retardation of cell death by blocking capsaicin-induced ER stress-mediated apoptosis in MCF-7 and MDA-MB-321 cells.
authors.affiliation: Research Center for Resistant Cells, College of Medicine, Chosun University, Seosuk-dong, Dong-gu, Gwangju 501-759, Korea.
authors.forename: Cheol-Hee
authors.initials: CH
authors.lastname: Choi
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
authors.forename: Seon-Hee
authors.initials: SH
authors.lastname: Oh
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D001483:Base Sequence; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D002211:Capsaicin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002211:Capsaicin