c-Fos as a Proapoptotic Agent in TRAIL-Induced Apoptosis in Prostate Cancer Cells

Authors

• Xiaoping Zhang, Massachusetts General Hospital
• Liang Zhang, Harvard Medical School
• Hongmei Yang, Harvard Medical School
• Xu Huang, Harvard Medical School
• Hasan H. Otu, Harvard Medical SchoolFollow
• Towia A. Libermann, Harvard Medical School
• William C. DeWolf, Harvard Medical School
• Roya Khosravi-Far, Harvard Medical School
• Aria F. Olumi, Massachusetts General HospitalFollow

ORCID IDs

Hasan H. Otu

Document Type

Article

Date of this Version

2007

Citation

Cancer Res. 2007 October 1; 67(19): 9425–9434

Comments

doi:10.1158/0008-5472.CAN-07-1310

Abstract

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 TRAILbased proapoptotic therapies.