MAD2-induced sensitization to vincristine is associated with mitotic arrest and Raf/Bcl-2 phosphorylation in nasopharyngeal carcinoma cells.
Mitotic arrest deficient 2 (MAD2) is thought to be a key component of the mitotic checkpoint, which ensures accurate chromosome segregation. Reduced expression of MAD2 protein is associated with mitotic checkpoint abrogation and chromosomal instability in certain types of human cancers. To explore the possibility of developing a novel strategy for the treatment of cancer based on selective killing of mitotic checkpoint-defective or -competent cells, here we have investigated the effect of MAD2 expression on cellular sensitivity to checkpoint-targeting anticancer drugs. We reintroduced MAD2 protein in a mitotic checkpoint-defective nasopharyngeal carcinoma cell line, CNE2, using an inducible expression vector. We found that overexpression of MAD2 led to an increased sensitivity to vincristine, which was accompanied by increased mitotic index and G2/M cell cycle arrest. In addition, increased phosphorylation of Raf, MEK1/2 and Bcl-2 was observed in MAD2-overexpressing cells in response to vincristine. Furthermore, inhibition of phosphorylation of MEK1/2 by its inhibitor PD098059 led to reduced sensitivity to vincristine, which was associated with decreased Bcl-2 phosphorylation. Our data suggest a role for MAD2 in the sensitization of cancer cells to certain mitotic checkpoint-targeting anticancer drugs.
Wang
Xianghong
X
Department of Anatomy, Faculty of Medicine, Hong Kong.
Jin
Dong-Yan
DY
Wong
Hing Lok
HL
Feng
Huichen
H
Wong
Yong-Chuan
YC
Tsao
Sai Wah
SW
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000502:physiology*; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D005656:Fungal Proteins / Q000502:physiology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D009303:Nasopharyngeal Neoplasms / Q000473:pathology*; D009687:Nuclear Proteins; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D005656:Fungal Proteins; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014750:Vincristine; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases