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

被引:75
作者
Uddin, Shahab
Siraj, Abdul K.
Al-Rasheed, Maha
Ahmed, Maqbool
Bu, Rong
Myers, Jeffrey N. [5 ]
Al-Nuaim, Abdulrahman [2 ]
Al-Sobhi, Saif [3 ]
Al-Dayel, Fouad [4 ]
Bavi, Prashant
Hussain, Azhar R.
Al-Kuraya, Khawla S. [1 ]
机构
[1] King Faisal Specialist Hosp & Res Ctr, King Fahad Natl Ctr Childrens Canc & Res, Dept Human Canc Genom Res, Res Ctr, Riyadh 11211, Saudi Arabia
[2] King Faisal Specialist Hosp & Res Ctr, Dept Endocrinol, Riyadh 11211, Saudi Arabia
[3] King Faisal Specialist Hosp & Res Ctr, Dept Surg, Riyadh 11211, Saudi Arabia
[4] King Faisal Specialist Hosp & Res Ctr, Dept Pathol, Riyadh 11211, Saudi Arabia
[5] Univ Texas Houston, MD Anderson Canc Ctr, Dept Head & Neck Surg, Houston, TX 77030 USA
关键词
D O I
10.1210/jc.2008-0503
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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收藏
页码:4088 / 4097
页数:10
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