title: JNK interacting protein 1 (JIP-1) protects LNCaP prostate cancer cells from growth arrest and apoptosis mediated by 12-0-tetradecanoylphorbol-13-acetate (TPA).
abstract: 12-0-tetradecanoylphorbol-13-acetate (TPA) stimulates protein kinase C (PKC) which mediates apoptosis in androgen-sensitive LNCaP human prostate cancer cells. The downstream signals of PKC that mediate TPA-induced apoptosis in LNCaP cells are unclear. In this study, we found that TPA activates the c-Jun NH2-terminal kinase (JNK)/c-Jun/AP-1 pathway. To explore the possible role that the JNK/c-Jun/AP-1 signal pathway has on TPA-induced apoptosis in LNCaP cells, we stably transfected the scaffold protein, JNK interacting protein 1 (JIP-1), which binds to JNK inhibiting its ability to phosphorylate c-Jun. TPA (10(-9)-10(-7) mol l(-1)) caused phosphorylation of JNK in both wild-type and JIP-1-transfected (LNCaP-JIP-1) cells. It resulted in phosphorylation and upregulation of expression of c-Jun protein in the wild-type LNCaP cells, but not in the JIP-1-transfected LNCaP cells. In addition, upregulation of AP-1 reporter activity by TPA (10(-9) mol l(-1)) occurred in LNCaP cells but was abrogated in LNCaP-JIP-1 cells. Thus, TPA stimulated c-Jun through JNK, and JIP-1 effectively blocked JNK. TPA (10(-12)-10(-8) mol l(-1)) treatment of LNCaP cells caused their growth inhibition, cell cycle arrest, upregulation of p53 and p21waf1, and induction of apoptosis. All of these effects were significantly attenuated when LNCaP-JIP-1 cells were similarly treated with TPA. A previous study showed that c-Jun/AP-1 blocked androgen receptor (AR) signaling by inhibiting AR binding to AR response elements (AREs) of target genes including prostate-specific antigen (PSA). Therefore, we hypothesised that TPA would not be able to disrupt the AR signal pathway in LNCaP-JIP-1 cells. Contrary to expectation, TPA (10(-9)-10(-8) mol l(-1)) inhibited DHT-induced AREs reporter activity and decreased levels of PSA in the LNCaP-JIP-1 cells. Taken together, TPA, probably by stimulation of PKC, phosphorylates JNK, which phosphorylates and increases expression of c-Jun leading to AP-1 activity. Growth control of prostate cancer cells can be mediated through the JNK/c-Jun pathway, but androgen responsiveness of these cells can be independent of this pathway, suggesting that androgen independence in progressive prostate cancer may not occur through activation of this pathway.
authors.affiliation: Division of Hematology/Oncology, Cedars-Sinai Research Institute, University of California-Los Angeles School of Medicine, Los Angeles, CA 90048, USA. ikezoet@med.kochi-ms.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Ikezoe
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: H
authors.initials: H
authors.lastname: Taguchi
authors.forename: H P
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000728:Androgens / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008297:Male; D010957:Plasmids; D017430:Prostate-Specific Antigen / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000728:Androgens; D002273:Carcinogens; D002352:Carrier Proteins; C490666:MAPK8IP1 protein, human; D017430:Prostate-Specific Antigen; D013755:Tetradecanoylphorbol Acetate