標題: Targeting the XIAP/caspase-7 complex selectively kills caspase-3-deficient malignancies
作者: Lin, Yuan-Feng
Lai, Tsung-Ching
Chang, Chih-Kang
Chen, Chi-Long
Huang, Ming-Shyan
Yang, Chih-Jen
Liu, Hon-Ge
Dong, Jhih-Jhong
Chou, Yi-An
Teng, Kuo-Hsun
Chen, Shih-Hsun
Tian, Wei-Ting
Jan, Yi-Hua
Hsiao, Michael
Liang, Po-Huang
生物科技學系
Department of Biological Science and Technology
公開日期: 1-九月-2013
摘要: Caspase-3 downregulation (CASP3/DR) in tumors frequently confers resistance to cancer therapy and is significantly correlated with a poor prognosis in cancer patients. Because CASP3/DR cancer cells rely heavily on the activity of caspase-7 (CASP7) to initiate apoptosis, inhibition of activated CASP7 (p19/p12-CASP7) by X-linked inhibitor of apoptosis protein (XIAP) is a potential mechanism by which apoptosis is prevented in those cancer cells. Here, we identify the pocket surrounding the Cys(246) residue of p19/p12-CASP7 as a target for the development of a protein-protein interaction (PPI) inhibitor of the XIAP:p19/p12-CASP7 complex. Interrupting this PPI directly triggered CASP7-dependent apoptotic signaling that bypassed the activation of the apical caspases and selectively killed CASP3/DR malignancies in vitro and in vivo without adverse side effects in nontumor cells. Importantly, CASP3/DR combined with p19/p12-CASP7 accumulation correlated with the aggressive evolution of clinical malignancies and a poor prognosis in cancer patients. Moreover, targeting of this PPI effectively killed cancer cells with multidrug resistance due to microRNA let-7a-1-mediated CASP3/DR and resensitized cancer cells to chemotherapy-induced apoptosis. These findings not only provide an opportunity to treat CASP3/DR malignancies by targeting the XIAP:p19/p12-CASP7 complex, but also elucidate the molecular mechanism underlying CASP3/DR in cancers.
URI: http://dx.doi.org/10.1172/JCI67951
http://hdl.handle.net/11536/22775
ISSN: 0021-9738
DOI: 10.1172/JCI67951
期刊: JOURNAL OF CLINICAL INVESTIGATION
Volume: 123
Issue: 9
起始頁: 3861
結束頁: 3875
顯示於類別:期刊論文


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