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J Clin Endocrinol Metab. 2008 Oct;93(10):4088-97. doi: 10.1210/jc.2008-0503. Epub 2008 Aug 5.

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

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1
Department of Human Cancer Genomic Research, King Fahad National Center for Children's Cancer and Research, King Faisal Specialist Hospital and Research Cancer, Riyadh 11211, Saudi Arabia.

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.

PMID:
18682509
DOI:
10.1210/jc.2008-0503
[Indexed for MEDLINE]
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