title: Dual effect of capsaicin on cell death in human osteosarcoma G292 cells.
abstract: Thirty percent of osteosarcoma patients die within 5 years. New agents that induce apoptosis of osteosarcoma cells might be therapeutically useful. Here, we characterized the apoptotic mechanism induced by capsaicin in G292 osteosarcoma cells. Our results show that capsaicin induces an increase in the cytosolic Ca(2+) concentration which is independent of the extracellular Ca(2+) concentration and depletes intracellular Ca(2+) stores, suggesting the presence of endoplasmic reticulum transient receptor potential vanilloid receptor type 1. Capsaicin also activates the mitochondrial caspase 3-dependent death cascade. Rapamycin, an inhibitor of mammalian target of rapamycin, evokes autophagy, as do capsaicin or thapsigargin, a sarco(endo)plasmic reticulum Ca(2+) ATPase inhibitor that causes Ca(2+) store depletion. Capsaicin-induced cell death is completely inhibited by co-treatment with the pan-caspase inhibitor Z-VAD-fmk and increased by the autophagy inhibitor 3-methyladenine, suggesting the existence of an autophagy-dependent anti-apoptotic mechanism. Capsaicin also induces ERK phosphorylation, which acts as a downstream effector of autophagy. 3-Methyladenine or PD98059, an ERK kinase inhibitor, restores capsaicin-induced cell death in the presence of Z-VAD-fmk, suggesting that inhibition of autophagy activates a second cell death pathway that is caspase-independent. Taken together, our data show that capsaicin causes Ca(2+) depletion of intracellular Ca(2+) stores and simultaneously activates the mitochondrial caspase-dependent death cascade and autophagy-dependent ERK activation and that the latter counteracts a second death signaling pathway that is caspase-independent.
authors.affiliation: Department of Orthopaedics, Chi Mei Medical Center, Tainan, Taiwan, ROC. Electronic address: Jannie.gissing@msa.hinet.net.
authors.forename: Chi-Sheng
authors.initials: CS
authors.lastname: Chien
authors.forename: Kuo-Hsing
authors.initials: KH
authors.lastname: Ma
authors.forename: Herng-Sheng
authors.initials: HS
authors.lastname: Lee
authors.forename: Pei-Shan
authors.initials: PS
authors.lastname: Liu
authors.forename: Yui-Huei
authors.initials: YH
authors.lastname: Li
authors.forename: Yu-Shiuan
authors.initials: YS
authors.lastname: Huang
authors.forename: Sheau-Huei
authors.initials: SH
authors.lastname: Chueh
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D010006:Osteoblasts / Q000473:pathology; D012516:Osteosarcoma / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D002211:Capsaicin
keywords: Apoptosis; Autophagy; Capsaicin; Osteosarcoma; Transient receptor potential vanilloid receptor