Fatty acid synthase and AKT pathway signaling in a subset of papillary thyroid cancers

Shahab Uddin, Abdul K. Siraj, Maha Al-Rasheed, Maqbool Ahmed, Rong Bu, Jeffrey N. Myers, Abdulrahman Al-Nuaim, Saif Al-Sobhi, Fouad Al-Dayel, Prashant Bavi, Azhar R. Hussain, Khawla S. Al-Kuraya

Research output: Contribution to journalArticlepeer-review

67 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4088-4097
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume93
Issue number10
DOIs
Publication statusPublished - Oct 2008
Externally publishedYes

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