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.