title: The WWP1 ubiquitin E3 ligase increases TRAIL resistance in breast cancer.
abstract: WW domain containing E3 ubiquitin protein ligase 1 (WWP1) is an HECT domain-containing E3 ligase regulating apoptosis. The WWP1 gene is frequently amplified and overexpressed in estrogen receptor α (ERα)-positive breast cancer. Inhibition of WWP1 by siRNA induced apoptosis in MCF7 and HCC1500. In our study, we demonstrate that WWP1 depletion by siRNA activated the extrinsic apoptotic pathway. WWP1 depletion-induced apoptosis was rescued by the overexpression of the wild-type WWP1 but not the E3 ligase inactive WWP1-C890A mutant in MCF7 cells. In contrast, WWP1-C890A enhanced apoptosis, suggesting that the E3 ligase activity is required for WWP1 to promote cell survival. The expression levels of WWP1 in four breast cancer cell lines were specifically correlated with the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resistance, but not TNFα and doxorubicin resistance. Both WWP1 depletion and dominant negative WWP1 overexpression increased the TRAIL-induced caspase-8 recruitment and apoptosis although WWP1 did not regulate FLIP and death receptor levels. Depletion of the initial caspase-8 blocked WWP1 inhibition-induced apoptosis in MCF7. These findings suggest that inhibition of WWP1 may be combined with TRAIL to suppress ERα-positive breast cancer cell survival.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.
authors.forename: Zhongmei
authors.initials: Z
authors.lastname: Zhou
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.forename: Ceshi
authors.initials: C
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D053218:Receptors, Death Domain / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D034741:RNA, Small Interfering; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; C471642:WWP1 protein, human; D044767:Ubiquitin-Protein Ligases; D053181:Caspase 8