RT Journal Article
SR Electronic
T1 Autophagy Induction by Capsaicin in Malignant Human Breast Cells is Modulated by p38 and ERK Mitogen-Activated Protein Kinases and Retards Cell Death by Suppressing Endoplasmic Reticulum Stress-Mediated Apoptosis
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.063495
DO 10.1124/mol.110.063495
A1 SeonHee Oh
A1 Cheol-Hee Choi
A1 Yong-Keun Jung
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/04/06/mol.110.063495.abstract
AB 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 non-apoptotic 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 ER stress via inositol-requiring 1 and Chop, and induced autophagy, as demonstrated by 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 over 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 downregulated capsaicin-induced p38 activation and LC3 conversion, and BaF1 completely downregulated ERK activation and led to LC3II accumulation. In addition, pharmacological blockade or knockdown of the p38 gene downregulated Akt activation and LC3II levels, but did not affect ERK, and pharmacological blockade or knockdown of the ERK gene upregulated LC3II induction by capsaicin. Knockdown of inositol-requiring 1 downregulated 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, while 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.The American Society for Pharmacology and Experimental Therapeutics