Oxaliplatin enhances TRAIL-induced apoptosis in gastric cancer cells by CBL-regulated death receptor redistribution in lipid rafts.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family that selectively induces apoptosis in cancer cells. However, gastric cancer cells are insensitive to TRAIL. In the present study, we show that oxaliplatin enhanced TRAIL-induced apoptosis of MGC803, BGC823, and SGC7901 cells. Oxaliplatin promoted death receptor 4 (DR4) and death receptor 5 (DR5) clustering into aggregated lipid rafts, while the cholesterol-sequestering agent nystatin partially prevented lipid raft aggregation, DR4 and DR5 clustering, and reduced apoptosis. Furthermore, the expression of the casitas B-lineage lymphoma (Cbl) family was downregulated by oxaliplatin. Transfection of c-Cbl or Cbl-b partially reversed oxaliplatin-induced lipid raft aggregation. These results indicated that oxaliplatin enhanced TRAIL-induced gastric cancer cell apoptosis at least partially through Cbl-regulated death receptor redistribution in lipid rafts.
Xu
Ling
L
Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China.
Qu
Xiujuan
X
Zhang
Ye
Y
Hu
Xuejun
X
Yang
Xianghong
X
Hou
Kezuo
K
Teng
Yuee
Y
Zhang
Jingdong
J
Sada
Kiyonao
K
Liu
Yunpeng
Y
D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D009761:Nystatin / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D053218:Receptors, Death Domain / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D009944:Organoplatinum Compounds; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077150:Oxaliplatin; D009761:Nystatin; D050721:Proto-Oncogene Proteins c-cbl