[HTML][HTML] Targeting the XIAP/caspase-7 complex selectively kills caspase-3–deficient malignancies
YF Lin, TC Lai, CK Chang, CL Chen… - The Journal of …, 2013 - Am Soc Clin Investig
YF Lin, TC Lai, CK Chang, CL Chen, MS Huang, CJ Yang, HG Liu, JJ Dong, YA Chou…
The Journal of Clinical Investigation, 2013•Am Soc Clin InvestigCaspase-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 …
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 …
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.
The Journal of Clinical Investigation