title: Curcumin induces apoptosis in human gastric carcinoma AGS cells and colon carcinoma HT-29 cells through mitochondrial dysfunction and endoplasmic reticulum stress.
abstract: In the present study, we investigate the effect of curcumin, a major active component isolated from rhizomes of Curcuma longa, on the cytotoxicity of three human carcinoma cell lines (AGS, HT-29 and MGC803) in gastrointestinal tract and a normal gastric epithelial cell line GES-1, and the mechanism of curcumin-induced apoptosis. The results indicated that curcumin inhibited the gastrointestinal carcinoma cell growth in a dose-dependent manner and cytotoxicity was more towards the gastric carcinoma cell AGS and colon carcinoma cell HT-29 compared to normal gastric cell GES-1, and increased externalization of phosphatidylserine residue was observed by Annexin V/PI staining in the two cell lines. Treatment of AGS and HT-29 cells with curcumin enhanced the cleavage of procaspase-3, -7, -8 and -9. Meanwhile, curcumin induced endoplasmic reticulum (ER) stress and mitochondrial dysfunction as evidenced by up-regulation of CCAAT/enhancer binding protein homologous protein (CHOP), phosphorylation of JNK and down-regulation of SERCA2ATPase, release of cytochrome c, decrease of Bcl-2 and reduction of mitochondrial membrane potential in both AGS and HT-29 cells. Overexpression of bax, total JNK, phospho-FADD and total FADD were also observed in curcumin-treated HT-29 cells. Moreover, curcumin decreased cytosolic and ER Ca(2+), but increased mitochondrial Ca(2+) in the two cell lines. 2-Aminoethoxydiphenyl borate, an antagonist of inositol 1, 4, 5-triphosphate receptor, partly blocked curcumin-induced cytosolic Ca(2+) decrease in AGS and HT-29 cells. Additionally, carbonyl cyanide m-chlorophenylhydrazone, an inhibitor of mitochondrial Ca(2+) uptake, reversed curcumin-triggered AGS and HT-29 cells growth inhibition. siRNA to CHOP markedly reduced curcumin-induced apoptosis. These results suggest that curcumin can impact on ER stress and mitochondria functional pathways in AGS and HT-29 cells, death receptor pathway was also involved in curcumin-treated HT-29 cells, thus identifying specific well-defined molecular mechanisms that may be targeted by therapeutic strategies.
authors.affiliation: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Aili
authors.initials: A
authors.lastname: Cao
authors.affiliation: Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
authors.forename: Peihao
authors.initials: P
authors.lastname: Yin
authors.affiliation: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Hailian
authors.initials: H
authors.lastname: Shi
authors.affiliation: Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Ji
authors.affiliation: Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China. xiejq01@gmail.com.
authors.forename: Jianqun
authors.initials: J
authors.lastname: Xie
authors.affiliation: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. wdazheng@vip.sina.com.|Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China. wdazheng@vip.sina.com.
authors.forename: Dazheng
authors.initials: D
authors.lastname: Wu
mesh_terms: D017304:Annexin A5; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004396:Coloring Agents; D030024:Curcuma / Q000737:chemistry; D003474:Curcumin / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D017304:Annexin A5; D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; C497249:DDIT3 protein, human; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D010936:Plant Extracts; D034741:RNA, Small Interfering; D051742:Transcription Factor CHOP; D048670:MAP Kinase Kinase 4; D020169:Caspases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D003474:Curcumin; D002118:Calcium