Repression of NF-κB and activation of AP-1 enhance apoptosis in prostate cancer cells

Abstract

TNFα 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 TNFα and TRAIL. We show that inhibition of NF-κB or activation of AP-1 can only partially sensitize resistant prostate cancer cells to proapoptotic effects of TNFα or TRAIL. Inhibition of NF-́B by silencing TRAF2, by silencing RIP or by ectopic expression of ÍB partially sensitized resistant prostate cancer. Similarly, activation of c-Fos/AP-1 only partially sensitized resistant cancer cells to proapoptotic effects of TNFα or TRAIL. However, concomitant repression of NF-κB and activation of c-Fos/AP-1 significantly enhanced the proapoptotic effects of TNFα 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. © 2008 Wiley-Liss, Inc.