title: 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: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors: Yuan-Feng
authors: YF
authors: Lin
authors: Tsung-Ching
authors: TC
authors: Lai
authors: Chih-Kang
authors: CK
authors: Chang
authors: Chi-Long
authors: CL
authors: Chen
authors: Ming-Shyan
authors: MS
authors: Huang
authors: Chih-Jen
authors: CJ
authors: Yang
authors: Hon-Ge
authors: HG
authors: Liu
authors: Jhih-Jhong
authors: JJ
authors: Dong
authors: Yi-An
authors: YA
authors: Chou
authors: Kuo-Hsun
authors: KH
authors: Teng
authors: Shih-Hsun
authors: SH
authors: Chen
authors: Wei-Ting
authors: WT
authors: Tian
authors: Yi-Hua
authors: YH
authors: Jan
authors: Michael
authors: M
authors: Hsiao
authors: Po-Huang
authors: PH
authors: Liang
mesh_terms: D000478:Alkylation; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000201:enzymology / Q000401:mortality; D053148:Caspase 3 / Q000172:deficiency* / Q000235:genetics; D053179:Caspase 7 / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000401:mortality; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000201:enzymology / Q000401:mortality; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D060066:Protein Interaction Maps; D015398:Signal Transduction; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D008239:Lysine
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