title: PCTAIRE1-knockdown sensitizes cancer cells to TNF family cytokines.
abstract: While PCTAIRE1/PCTK1/Cdk16 is overexpressed in malignant cells and is crucial in tumorigenesis, its function in apoptosis remains unclear. Here we investigated the role of PCTAIRE1 in apoptosis, especially in the extrinsic cell death pathway. Gene-knockdown of PCTAIRE1 sensitized prostate cancer PPC1 and Du145 cells, and breast cancer MDA-MB-468 cells to TNF-family cytokines, including TNF-related apoptosis-inducing ligand (TRAIL). Meanwhile, PCTAIRE1-knockdown did not sensitize non-malignant cells, including diploid fibroblasts IMR-90 and the immortalized prostate epithelial cell line 267B1. PCTAIRE1-knockdown did not up-regulate death receptor expression on the cell surface or affect caspase-8, FADD and FLIP expression levels. PCTAIRE1-knockdown did promote caspase-8 cleavage and RIPK1 degradation, while RIPK1 mRNA knockdown sensitized PPC1 cells to TNF-family cytokines. Furthermore, the kinase inhibitor SNS-032, which inhibits PCTAIRE1 kinase activity, sensitized PPC1 cells to TRAIL-induced apoptosis. Together these results suggest that PCTAIRE1 contributes to the resistance of cancer cell lines to apoptosis induced by TNF-family cytokines, which implies that PCTAIRE1 inhibitors could have synergistic effects with TNF-family cytokines for cytodestruction of cancer cells.
authors: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California, United States of America.
authors: Teruki
authors: T
authors: Yanagi
authors: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California, United States of America.
authors: Ranxin
authors: R
authors: Shi
authors: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California, United States of America.
authors: Pedro
authors: P
authors: Aza-Blanc
authors: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California, United States of America.
authors: John C
authors: JC
authors: Reed
authors: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California, United States of America.
authors: Shu-ichi
authors: S
authors: Matsuzawa
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D010080:Oxazoles / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D016207:Cytokines; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; C484864:N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide; D010080:Oxazoles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D013844:Thiazoles; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases; C089463:PCTAIRE-1 protein kinase; D053181:Caspase 8