Targeting the XIAP/caspase-7 complex selectively kills caspase-3-deficient malignancies

Yuan-Feng Lin, Tsung Ching Lai, Chih Kang Chang, Chi Long Chen, Ming Shyan Huang, Chih Jen Yang, Hon Ge Liu, Jhih Jhong Dong, Yi An Chou, Kuo Hsun Teng, Shih Hsun Chen, Wei Ting Tian, Yi Hua Jan, Michael Hsiao, Po Huang Liang

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14 Citations (Scopus)

Abstract

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 Cys246 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.

Original languageEnglish
Pages (from-to)3861-3875
Number of pages15
JournalJournal of Clinical Investigation
Volume123
Issue number9
DOIs
Publication statusPublished - Sep 3 2013

ASJC Scopus subject areas

  • Medicine(all)

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    Lin, Y-F., Lai, T. C., Chang, C. K., Chen, C. L., Huang, M. S., Yang, C. J., Liu, H. G., Dong, J. J., Chou, Y. A., Teng, K. H., Chen, S. H., Tian, W. T., Jan, Y. H., Hsiao, M., & Liang, P. H. (2013). Targeting the XIAP/caspase-7 complex selectively kills caspase-3-deficient malignancies. Journal of Clinical Investigation, 123(9), 3861-3875. https://doi.org/10.1172/JCI67951