Repression of NF-kappaB and activation of AP-1 enhance apoptosis in prostate cancer cells.
TNFalpha and TRAIL, 2 members of the tumor necrosis factor family, share many common signaling pathways to induce apoptosis. Although many cancer cells are sensitive to these proapoptotic agents, some develop resistance. Recently, we have demonstrated that upregulation of c-Fos/AP-1 is necessary, but insufficient for cancer cells to undergo TRAIL-induced apoptosis. Here we present a prostate cancer model with differential sensitivity to TNFalpha and TRAIL. We show that inhibition of NF-kappaB or activation of AP-1 can only partially sensitize resistant prostate cancer cells to proapoptotic effects of TNFalpha or TRAIL. Inhibition of NF-kappaB by silencing TRAF2, by silencing RIP or by ectopic expression of IkappaB partially sensitized resistant prostate cancer. Similarly, activation of c-Fos/AP-1 only partially sensitized resistant cancer cells to proapoptotic effects of TNFalpha or TRAIL. However, concomitant repression of NF-kappaB and activation of c-Fos/AP-1 significantly enhanced the proapoptotic effects of TNFalpha and TRAIL in resistant prostate cancer cells. Therefore, multiple molecular pathways may need to be modified, to overcome cancers that are resistant to proapoptotic therapies.
Zhang
Xiaoping
X
Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Huang
Xu
X
Olumi
Aria F
AF
D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016328:NF-kappa B; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha