Matrix protein CCN1 is critical for prostate carcinoma cell proliferation and TRAIL-induced apoptosis.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plays an important role in immune surveillance and preferentially induces apoptosis in cancer cells over normal cells, suggesting its potential in cancer therapy. However, the molecular basis for its selective killing of cancer cells is not well understood. Recent studies have identified the CCN family of integrin-binding matricellular proteins as important regulators of cell behavior, including cell adhesion, proliferation, migration, differentiation, and survival. We show here that CCN1 (CYR61) supports the adhesion of prostatic carcinoma cells as an adhesion substrate through integrins and heparan sulfate proteoglycans. Knockdown of CCN1 expression in PC-3 and DU-145 androgen-independent prostate cancer cells strongly inhibited their proliferation without causing apoptosis, indicating that CCN1 promotes their growth. However, CCN1 also significantly enhances TRAIL-induced apoptosis through interaction with integrins alphavbeta3 and alpha6beta4 and the cell-surface heparan sulfate proteoglycan syndecan-4, acting through a protein kinase Calpha-dependent mechanism without requiring de novo protein synthesis. Knockdown of CCN1 expression in PC-3, DU-145, and LNCaP cells severely blunted their sensitivity to TRAIL, an effect that was reversed by exogenously added CCN1 protein. These findings reveal a functional dichotomy for CCN1 in prostate carcinoma cells, because it contributes to both cell proliferation and TRAIL-induced cell death and suggest that CCN1 expression status may be an important parameter in assessing the efficacy of TRAIL-dependent cancer therapy.
Franzen
Carrie A
CA
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine, Chicago, IL 60607, USA.
Chen
Chih-Chiun
CC
Todorović
Viktor
V
Juric
Vladislava
V
Monzon
Ricardo I
RI
Lau
Lester F
LF
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051571:Protein Kinase C-alpha / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000494:pharmacology*
C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D019812:Heparan Sulfate Proteoglycans; D016023:Integrins; D017382:Reactive Oxygen Species; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051571:Protein Kinase C-alpha