Targeting the XIAP/caspase-7 complex selectively kills caspase-3–deficient malignancies
Yuan-Feng Lin, … , Michael Hsiao, Po-Huang Liang
Yuan-Feng Lin, … , Michael Hsiao, Po-Huang Liang
Published August 27, 2013
Citation Information: J Clin Invest. 2013;123(9):3861-3875. https://doi.org/10.1172/JCI67951.
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Research Article

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

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.

Authors

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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Figure 6

p19/p12-CASP7 accumulates in CASP3/DR malignancies and is closely associated with disease progression.

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p19/p12-CASP7 accumulates in CASP3/DR malignancies and is closely associ...
(A) IHC analysis of CASP3 and p19/p12-CASP7 expression in 2 representative groups of clinical breast, lung, and colon cancer specimens. Original magnification, ×400. R values and statistical significance, calculated using Pearson correlation analysis, are shown at right. Negative R values indicate that CASP3 and p19/p12-CASP7 expression levels are inversely correlated in clinical cancer samples. (B) IHC analysis of CASP3 and p19/p12-CASP7 expression in 2 serial sections of representative colon cancer tissue. Morphologically benign (B) and malignant (M) regions are indicated. Original magnification, ×200. (C) Kaplan-Meier analyses of survival probabilities in cohorts of patients with breast, lung, and colon cancer expressing combined low-level CASP3 and high-level p19/p12-CASP7 compared with other signatures. Log-rank tests were used to determine statistical significance.