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MG-132 Sensitizes TRAIL-Resistant Prostate Cancer Cells by Activating c-Fos/c-Jun Heterodimers and Repressing c-FLIP(L)

Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Aria F. Olumi, Department of Urology, Massachusetts General Hospital, Harvard Medical School, Yawkey Building, Suite 7E, 55 Fruit St., Boston, MA 02114. Phone: 617-643-0237; E-mail: aolumi{at}partners.org.

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent because it induces apoptosis in cancer cells but not in normal cells. Unfortunately, some cancer cells develop resistance to TRAIL-induced apoptosis. Therefore, it is clinically relevant to determine the molecular mechanisms that differentiate between TRAIL-sensitive and TRAIL-resistant tumors. Previously, we have shown that the antiapoptotic molecule cellular-FLICE-inhibitory protein long isoform [c-FLIP(L)] is necessary and sufficient to maintain resistance to TRAIL-induced apoptosis. We have found that c-FLIP(L) is transcriptionally regulated by the activator protein-1 (AP-1) family member protein c-Fos. Here, we report that MG-132, a small-molecule inhibitor of the proteasome, sensitizes TRAIL-resistant prostate cancer cells by inducing c-Fos and repressing c-FLIP(L). c-Fos, which is activated by MG-132, negatively regulates c-FLIP(L) by direct binding to the putative promoter region of the c-FLIP(L) gene. In addition to activating c-Fos, MG-132 activates another AP-1 family member, c-Jun. We show that c-Fos heterodimerizes with c-Jun to repress transcription of c-FLIP(L). Therefore, MG-132 sensitizes TRAIL-resistant prostate cancer cells by activating the AP-1 family members c-Fos and c-Jun, which, in turn, repress the antiapoptotic molecule c-FLIP(L). [Cancer Res 2007;67(5):2247–55]

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