1. ¹Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain
2. ²Cell signalling and Apoptosis Group, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain
3. ³Department of Gynecology, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain

Correspondence: Dr X Dolcet, Laboratori de Recerca Biomèdica, Hospital University Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Av Rovira Roure 80, Lleida 25198, Spain. E-mail: dolcet@cmb.udl.es

⁴These are the senior co-authors.

Received 21 August 2007; Revised 15 October 2007; Accepted 17 October 2007; Published online 5 November 2007.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as a promising antineoplastic agent because of its ability to selectively kill tumoral cells. However, some cancer cells are resistant to TRAIL-induced apoptosis. We have previously demonstrated that in endometrial carcinoma cells such resistance is caused by elevated FLICE-inhibitory protein (FLIP) levels. The present study focuses on the mechanisms by which FLIP could be modulated to sensitize endometrial carcinoma cells to TRAIL-induced apoptosis. We find that inhibition of casein kinase (CK2) sensitizes endometrial carcinoma cells to TRAIL- and Fas-induced apoptosis. CK2 inhibition correlates with a reduction of FLIP protein, suggesting that CK2 regulates resistance to TRAIL and Fas by controlling FLIP levels. FLIP downregulation correlates with a reduction of mRNA and is prevented by addition of the MG-132, suggesting that CK2 inhibition results in a proteasome-mediated degradation of FLIP. Consistently, forced expression of FLIP restores resistance to TRAIL and Fas. Moreover, knockdown of either FADD or caspase-8 abrogates apoptosis triggered by inhibition of CK2, indicating that CK2 sensitization requires formation of functional DISC. Finally, because of the possible role of both TRAIL and CK2 in cancer therapy, we demonstrate that CK2 inhibition sensitizes primary endometrial carcinoma explants to TRAIL apoptosis. In conclusion, we demonstrate that CK2 regulates endometrial carcinoma cell sensitivity to TRAIL and Fas by regulating FLIP levels.