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.