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-Sep-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 |
Appears in Collections: | Articles |
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