title: c-Fos as a proapoptotic agent in TRAIL-induced apoptosis in prostate cancer cells.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2L promotes apoptosis in cancer cells while sparing normal cells. Although many cancers are sensitive to TRAIL-induced apoptosis, some evade the proapoptotic effects of TRAIL. Therefore, differentiating molecular mechanisms that distinguish between TRAIL-sensitive and TRAIL-resistant tumors are essential for effective cancer therapies. Here, we show that c-Fos functions as a proapoptotic agent by repressing the antiapoptotic molecule c-FLIP(L). c-Fos binds the c-FLIP(L) promoter, represses its transcriptional activity, and reduces c-FLIP(L) mRNA and protein levels. Therefore, c-Fos is a key regulator of c-FLIP(L), and activation of c-Fos determines whether a cancer cell will undergo cell death after TRAIL treatment. Strategies to activate c-Fos or inhibit c-FLIP(L) may potentiate TRAIL-based proapoptotic therapies.
authors.affiliation: Department of Urology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Hongmei
authors.initials: H
authors.lastname: Yang
authors.forename: Xu
authors.initials: X
authors.lastname: Huang
authors.forename: Hasan
authors.initials: H
authors.lastname: Otu
authors.forename: Towia A
authors.initials: TA
authors.lastname: Libermann
authors.forename: William C
authors.initials: WC
authors.lastname: DeWolf
authors.forename: Roya
authors.initials: R
authors.lastname: Khosravi-Far
authors.forename: Aria F
authors.initials: AF
authors.lastname: Olumi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D018808:Transcription Factor AP-1