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Melatonin sensitizes Caki renal cancer cells to kahweol‐induced apoptosis through CHOP‐mediated up‐regulation of PUMA
Author(s) -
Um Hee Jung,
Park JongWook,
Kwon Taeg Kyu
Publication year - 2011
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/j.1600-079x.2010.00851.x
Subject(s) - melatonin , puma , apoptosis , downregulation and upregulation , dna fragmentation , biology , microbiology and biotechnology , medicine , endocrinology , chemistry , programmed cell death , biochemistry , gene
Melatonin has recently gained attention as a regulator of biologic processes in addition to its effects on circadian rhythms. The mechanisms whereby melatonin regulates the apoptotic program remain poorly understood. In this study, we investigated the combined effect of melatonin and kahweol on apoptosis of cancer cells, but not in most normal human cell types, thus presenting an attractive novel strategy for cancer treatment. In our experiments, treatment with a combination of melatonin and kahweol induced apoptosis, stimulated DEVDase activity, and DNA fragmentation. Co‐treatment with melatonin and kahweol induced up‐regulation of p53‐upregulated modulator of apoptosis (PUMA) while down‐regulation of PUMA expression using small interfering RNAs attenuated melatonin plus kahweol‐induced apoptosis. In addition, co‐treatment with kahweol and melatonin induced PUMA up‐regulation through endoplasmic reticulum stress‐mediated C/EBP homologous protein induction and the p53‐independent pathway. Our results collectively demonstrate that up‐regulation of PUMA contributes to the sensitizing effect of melatonin plus kahweol on apoptosis in cancer cells.