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CK2 controls TRAIL and Fas sensitivity by regulating FLIP levels in endometrial carcinoma cells

LLOBET, D ; ERITJA, N ; ENCINAS, M ; LLECHA, N ; YERAMIAN, A ; PALLARES, J ; SOROLLA, A ; GONZALEZ-TALLADA, F. J ; MATIAS-GUIU, X ; DOLCET, X

Oncogene, 2008-04, Vol.27 (18), p.2513-2524 [Revista revisada por pares]

Basingstoke: Nature Publishing

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CK2 controls TRAIL and Fas sensitivity by regulating FLIP levels in endometrial carcinoma cells
Autor: LLOBET, D ; ERITJA, N ; ENCINAS, M ; LLECHA, N ; YERAMIAN, A ; PALLARES, J ; SOROLLA, A ; GONZALEZ-TALLADA, F. J ; MATIAS-GUIU, X ; DOLCET, X
Materias: Ageing, cell death ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Apoptosis ; Apoptosis - drug effects ; Apoptosis - genetics ; Biological and medical sciences ; Cancer ; Carcinoma ; Care and treatment ; Casein ; Casein Kinase II - antagonists & inhibitors ; Casein Kinase II - metabolism ; CASP8 and FADD-Like Apoptosis Regulating Protein - biosynthesis ; CASP8 and FADD-Like Apoptosis Regulating Protein - genetics ; Caspase-8 ; Cell Line ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Cellular biology ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - genetics ; Endometrial cancer ; Endometrial Neoplasms - drug therapy ; Endometrial Neoplasms - genetics ; Endometrial Neoplasms - metabolism ; Endometrial Neoplasms - pathology ; Endometrium ; Explants ; FADD protein ; fas Receptor - pharmacology ; fas Receptor - therapeutic use ; Female ; Female genital diseases ; FLICE-inhibitory protein ; FLIP protein ; Fundamental and applied biological sciences. Psychology ; Gene Expression Regulation, Neoplastic - drug effects ; Gene Expression Regulation, Neoplastic - genetics ; Genetic aspects ; Genetics ; Gynecology. Andrology. Obstetrics ; Humans ; Kinases ; Leupeptins - pharmacology ; Medical sciences ; Molecular and cellular biology ; mRNA ; Neoplasm Proteins - antagonists & inhibitors ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; Oncology ; Physiological aspects ; Proteasome Endopeptidase Complex - genetics ; Proteasome Endopeptidase Complex - metabolism ; Proteasomes ; Protein kinases ; Proteins ; Risk factors ; TNF-Related Apoptosis-Inducing Ligand - pharmacology ; TNF-Related Apoptosis-Inducing Ligand - therapeutic use ; TRAIL protein ; Tumor Cells, Cultured ; Tumors ; Uterine cancer
Es parte de: Oncogene, 2008-04, Vol.27 (18), p.2513-2524
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Descripción: 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.
Editor: Basingstoke: Nature Publishing
Idioma: Inglés

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CK2 controls TRAIL and Fas sensitivity by regulating FLIP levels in endometrial carcinoma cells

LLOBET, D ; ERITJA, N ; ENCINAS, M ; LLECHA, N ; YERAMIAN, A ; PALLARES, J ; SOROLLA, A ; GONZALEZ-TALLADA, F. J ; MATIAS-GUIU, X ; DOLCET, X

Basingstoke: Nature Publishing

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