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Fatty Acid Synthase and AKT Pathway Signaling in a Subset of Papillary Thyroid Cancers

Human Cancer Genomic Research (S.U., A.K.S., M.A.-R., M.A., R.B., P.B., A.R.H., K.S.A.-K.), King Fahad National Center for Children’s Cancer and Research, Research Center, and Departments of Endocrinology (A.A.-N.), Surgery (S.A.-S.), and Pathology (F.A.-D.), King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; and Department of Head and Neck Surgery (J.N.M.), M. D. Anderson Cancer Center, Texas 77030

Address all correspondence and requests for reprints to: Khawla S. Al-Kuraya, M.D., FCAP, Department of Human Cancer Genomic Research, King Fahad National Center for Children’s Cancer and Research, King Faisal Specialist Hospital and Research Cancer, MBC#98-16, P.O. Box 3354, Riyadh 11211, Saudi Arabia. E-mail: Kkuraya{at}kfshrc.edu.sa.

Context: Fatty acid synthase (FASN) is an enzyme that plays a critical role in de novo synthesis of fatty acids. FASN is overexpressed in variety of human cancers, but its role has not been elucidated in papillary thyroid carcinoma (PTC).

Objective: Our objective was to investigate the role of FASN and its relationship with phosphatidylinositol 3-kinase/AKT activation in a large series of PTC in a tissue microarray format followed by studies using PTC cell lines and Nude mice.

Design: Analysis of apoptosis and cell cycle were evaluated by flow cytometry and DNA fragmentation assays. FASN and phospho-AKT protein expression was determined by immunohistochemistry and Western blotting.

Results: Our data show that expression of FASN is associated with activated AKT (phospho-AKT) in a subset of PTC. Treatment of PTC cell lines (NPA-187, ONCO-DG-1, and B-CPAP) with C-75, an inhibitor of FASN, suppresses growth and induces apoptosis in all cell lines. Treatment of PTC cells with C-75 or expression of FASN small interfering RNA causes down-regulation of FASN and inactivation of AKT activity. Furthermore, treatment of PTC cell lines with C-75 results in apoptosis via the mitochondrial pathway involving the proapoptotic factor Bad, activation of Bax, activation of caspases, and down-regulation of antiapoptotic proteins. Finally, treatment of NPA-187 xenografts with C-75 results in growth inhibition of tumors in Nude mice via down-regulation of FASN expression and inactivation of AKT.

Conclusions: Our results suggest that FASN and activated AKT pathway may be a potential target for therapeutic intervention for the treatment of PTC.