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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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

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X-Linked Inhibitor of Apoptosis Protein
Caspase 7
Caspase 3
Down-Regulation
Neoplasms
Apoptosis
Proteins
Multiple Drug Resistance
Protein Transport
Caspases
MicroRNAs

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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

In: Journal of Clinical Investigation, Vol. 123, No. 9, 03.09.2013, p. 3861-3875.

Research output: Contribution to journalArticle

Lin, Y-F, Lai, TC, Chang, CK, Chen, CL, Huang, MS, Yang, CJ, Liu, HG, Dong, JJ, Chou, YA, Teng, KH, Chen, SH, Tian, WT, Jan, YH, Hsiao, M & Liang, PH 2013, 'Targeting the XIAP/caspase-7 complex selectively kills caspase-3-deficient malignancies', Journal of Clinical Investigation, vol. 123, no. 9, pp. 3861-3875. https://doi.org/10.1172/JCI67951
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. / Targeting the XIAP/caspase-7 complex selectively kills caspase-3-deficient malignancies. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 9. pp. 3861-3875.
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AU - Chen, Chi Long

AU - Huang, Ming Shyan

AU - Yang, Chih Jen

AU - Liu, Hon Ge

AU - Dong, Jhih Jhong

AU - Chou, Yi An

AU - Teng, Kuo Hsun

AU - Chen, Shih Hsun

AU - Tian, Wei Ting

AU - Jan, Yi Hua

AU - Hsiao, Michael

AU - Liang, Po Huang

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AB - 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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