c-Fos as a proapoptotic agent in TRAIL-induced apoptosis in prostate cancer cells.
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.
Zhang
Xiaoping
X
Department of Urology, Massachusetts General Hospital, Boston, MA 02114, USA.
Zhang
Liang
L
Yang
Hongmei
H
Huang
Xu
X
Otu
Hasan
H
Libermann
Towia A
TA
DeWolf
William C
WC
Khosravi-Far
Roya
R
Olumi
Aria F
AF
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
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