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Overexpression and overactivation of Akt in thyroid carcinoma
1Washington Hospital Center and MedStar Research Institute, Washington, DC 20010, USA. mxr9@mhg.edu
Abstract:
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.
Insights
Akt overactivation is common in sporadic thyroid cancer, particularly follicular types, suggesting its role in tumor development. This contrasts with Cowden's disease, where PTEN inactivation drives Akt activation, highlighting distinct pathways in thyroid cancer pathogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Cowden's disease involves Akt overactivation due to PTEN inactivation, leading to various tumors.
- PTEN inactivation is rare in sporadic thyroid cancer, but growth factor pathway activation through Akt is frequent.
- Akt signaling is implicated in cancer cell growth and survival.
Purpose of the Study:
- To investigate the prevalence and significance of Akt overactivation in sporadic thyroid cancer.
- To determine if Akt activation is a common event in thyroid cancer biology.
- To examine Akt isoform expression and activation in thyroid cancer cell lines and human tissues.
Main Methods:
- Analysis of Akt protein expression and phosphorylation in thyroid cancer cell lines.
- Examination of Akt activation and isoform levels in human benign and malignant thyroid tissues.
- Assessment of phosphatidylinositol 3'-kinase (PI3K) pathway involvement using insulin stimulation and PI3K inhibition.
Main Results:
- Akt 1, 2, and 3 proteins are expressed in thyroid cancer cells, with activation by insulin and PI3K inhibition reducing viability.
- Increased phosphorylated Akt levels were observed in follicular thyroid cancers but not papillary cancers compared to normal tissue.
- Elevated Akt 1 and 2 protein and Akt 2 RNA levels were specific to follicular cancers; Akt activation was higher in most paired cancer samples.
Conclusions:
- Akt activation appears to be a frequent event in sporadic thyroid cancer, especially follicular types.
- These findings suggest Akt overactivation may contribute to the pathogenesis or progression of sporadic thyroid cancer.
- Distinct mechanisms of Akt activation exist between inherited syndromes like Cowden's disease and sporadic thyroid cancers.