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


METHODS
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.
Uddin
Shahab
S
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.
Siraj
Abdul K
AK
Al-Rasheed
Maha
M
Ahmed
Maqbool
M
Bu
Rong
R
Myers
Jeffrey N
JN
Al-Nuaim
Abdulrahman
A
Al-Sobhi
Saif
S
Al-Dayel
Fouad
F
Bavi
Prashant
P
Hussain
Azhar R
AR
Al-Kuraya
Khawla S
KS
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002291:Carcinoma, Papillary / Q000145:classification / Q000188:drug therapy / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013964:Thyroid Neoplasms / Q000145:classification / Q000188:drug therapy / Q000235:genetics*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D004791:Enzyme Inhibitors; D064429:Fatty Acid Synthases; D051057:Proto-Oncogene Proteins c-akt; D015107:4-Butyrolactone