The ganglioside GM3 is associated with cisplatin-induced apoptosis in human colon cancer cells.
Cisplatin (cis-diamminedichloroplatinum, CDDP) is a well-known chemotherapeutic agent for the treatment of several cancers. However, the precise mechanism underlying apoptosis of cancer cells induced by CDDP remains unclear. In this study, we show mechanistically that CDDP induces GM3-mediated apoptosis of HCT116 cells by inhibiting cell proliferation, and increasing DNA fragmentation and mitochondria-dependent apoptosis signals. CDDP induced apoptosis within cells through the generation of reactive oxygen species (ROS), regulated the ROS-mediated expression of Bax, Bcl-2, and p53, and induced the degradation of the poly (ADP-ribosyl) polymerase (PARP). We also checked expression levels of different gangliosides in HCT116 cells in the presence or absence of CDDP. Interestingly, among the gangliosides, CDDP augmented the expression of only GM3 synthase and its product GM3. Reduction of the GM3 synthase level through ectopic expression of GM3 small interfering RNA (siRNA) rescued HCT116 cells from CDDP-induced apoptosis. This was evidenced by inhibition of apoptotic signals by reducing ROS production through the regulation of 12-lipoxigenase activity. Furthermore, the apoptotic sensitivity to CDDP was remarkably increased in GM3 synthase-transfected HCT116 cells compared to that in controls. In addition, GM3 synthase-transfected cells treated with CDDP exhibited an increased accumulation of intracellular ROS. These results suggest the CDDP-induced oxidative apoptosis of HCT116 cells is mediated by GM3.
Molecular and Cellular Glycobiology Laboratory, Department of Biological Science, SungKyunKwan University, Suwon City, Kyunggi-Do, Republic of Korea.
Tae-Wook
TW
Chung
Molecular and Cellular Glycobiology Laboratory, Department of Biological Science, SungKyunKwan University, Suwon City, Kyunggi-Do, Republic of Korea; Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan City, Gyeongsangnam-Do, Republic of Korea.
Hee-Jung
HJ
Choi
Molecular and Cellular Glycobiology Laboratory, Department of Biological Science, SungKyunKwan University, Suwon City, Kyunggi-Do, Republic of Korea.
Seok-Jo
SJ
Kim
Molecular and Cellular Glycobiology Laboratory, Department of Biological Science, SungKyunKwan University, Suwon City, Kyunggi-Do, Republic of Korea.
Choong-Hwan
CH
Kwak
Molecular and Cellular Glycobiology Laboratory, Department of Biological Science, SungKyunKwan University, Suwon City, Kyunggi-Do, Republic of Korea.
Kwon-Ho
KH
Song
Molecular and Cellular Glycobiology Laboratory, Department of Biological Science, SungKyunKwan University, Suwon City, Kyunggi-Do, Republic of Korea.
Un-Ho
UH
Jin
Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea.
Young-Chae
YC
Chang
Faculty of Pharmacy, Yeungnam University, Kyungsan, Republic of Korea.
Hyeun Wook
HW
Chang
Faculty of Medicinal Biotechnology, Dong-A University, Busan, Republic of Korea.
Young-Choon
YC
Lee
Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan City, Gyeongsangnam-Do, Republic of Korea.
Ki-Tae
KT
Ha
Molecular and Cellular Glycobiology Laboratory, Department of Biological Science, SungKyunKwan University, Suwon City, Kyunggi-Do, Republic of Korea.
Cheorl-Ho
CH
Kim
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005679:G(M3) Ganglioside / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012799:Sialyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D005679:G(M3) Ganglioside; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D001092:Arachidonate 12-Lipoxygenase; D011065:Poly(ADP-ribose) Polymerases; D012799:Sialyltransferases; C021343:haematoside synthetase; D002945:Cisplatin