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

Authors: 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 
Citation: Lin YF, etal., J Clin Invest. 2013 Sep;123(9):3861-75. doi: 10.1172/JCI67951. Epub 2013 Aug 27.
Pubmed: (View Article at PubMed) PMID:23979166
DOI: Full-text: DOI:10.1172/JCI67951

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.


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CRRD Object Information
CRRD ID: 13209143
Created: 2017-08-30
Species: All species
Last Modified: 2017-08-30
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.