Overexpression and overactivation of Akt in thyroid carcinoma.
Enhanced activation of Akt occurs in Cowden's disease, an inherited syndrome of follicular thyroid, breast, colon, and skin tumors, via inactivation of its regulatory protein, PTEN. Whereas PTEN inactivation is uncommon in sporadic thyroid cancer, activation of growth factor pathways that signal through Akt is frequently identified. We hypothesized that Akt overactivation could be a common finding in sporadic thyroid cancer and might be important in thyroid cancer biology. We examined thyroid cancer cells lines and benign and malignant thyroid tissue for total Akt activation and isoform-specific Akt expression. In thyroid cancer cells, Akt 1, 2, and 3 proteins were expressed, total Akt was activated by insulin phosphatidylinositol 3'-kinase, and inhibition of phosphatidylinositol 3'-kinase reduced cell viability. In human thyroid tissue, increased levels of phosphorylated total Akt were identified in follicular but not papillary cancers compared with normal tissue. Levels of Akt 1 and 2 proteins and Akt 2 RNA were elevated only in the follicular cancers. In paired samples, Akt 1, 2, 3, and phospho-Akt levels were higher in five of six cancers, including three of three follicular cancers. These data suggest that Akt activation may play a role in the pathogenesis or progression of sporadic thyroid cancer.
Ringel
M D
MD
Washington Hospital Center and MedStar Research Institute, Washington, DC 20010, USA. mxr9@mhg.edu
Hayre
N
N
Saito
J
J
Saunier
B
B
Schuppert
F
F
Burch
H
H
Bernet
V
V
Burman
K D
KD
Kohn
L D
LD
Saji
M
M
D018263:Adenocarcinoma, Follicular / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002291:Carcinoma, Papillary / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002470:Cell Survival / Q000502:physiology; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013961:Thyroid Gland / Q000201:enzymology; D013964:Thyroid Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013972:Thyrotropin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D007328:Insulin; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D013972:Thyrotropin; C494918:AKT1 protein, human; C494921:AKT2 protein, human