Switch in signaling control of mTORC1 activity after oncoprotein expression in thyroid cancer cell lines Journal Article
| Authors: | Malaguarnera, R.; Chen, K.; Kim, T.; DomÃnguez, J. M.; Voza, F.; Ouyang, B.; Vundavalli, S. K.; Knauf, J. A.; Fagin, J. A. |
| Article Title: | Switch in signaling control of mTORC1 activity after oncoprotein expression in thyroid cancer cell lines |
| Abstract: | Context: Thyroid growth is regulated by TSH and requires mammalian target of rapamycin (mTOR). Thyroid cancers frequently exhibit mutations in MAPK and/or phosphoinositol-3-kinase-related kinase effectors. Objective: The objective of the study was to explore the contribution of RET/PTC, RAS, and BRAF to mTOR regulation and response to mTOR inhibitors. Methods: PCCL3 cells conditionally expressing RET/PTC3, HRASG12V, or BRAFV600E and human thyroid cancer cells harboring mutations of these genes were usedtotest pathways controlling mTOR and its requirement for growth. Results: TSH/cAMP-induced growth of PCCL3 cells requires mTOR, which is stimulated via protein kinase A in a MAPK kinase (MEK)- and AKT-independent manner. Expression of RET/PTC3, HRASG12V, or BRAFV600E in PCCL3 cells induces mTOR but does not entirely abrogate the cAMP-mediated controlof its activity. Acute oncoprotein-induced mTOR activity is regulated by MEK and AKT, albeit to differing degrees. By contrast, mTOR was not activated by TSH/cAMP in human thyroid cancer cells. Tumor genotype did not predict the effects of rapamycin or the mTOR kinase inhibitor AZD8055 on growth, with the exception of a PTEN-null cell line. Selective blockade of MEK did not influence mTOR activity of BRAF or RAS mutant cells. Combined MEK and mTOR kinase inhibition was synergistic on growth of BRAF- and RAS-mutant thyroid cancer cells in vitro and in vivo. Conclusion: Thyroid cancer cells lose TSH/cAMP dependency of mTOR signaling and cell growth. mTOR activity is not decreased by the MEK or AKT inhibitors in the RAS or BRAF human thyroid cancer cell lines. This may account for the augmented effects of combining the mTOR inhibitors with selective antagonists of these oncogenic drivers. |
| Journal Title: | Journal of Clinical Endocrinology and Metabolism |
| Volume: | 99 |
| Issue: | 10 |
| ISSN: | 0021-972X |
| Publisher: | Oxford University Press |
| Date Published: | 2014-10-01 |
| Start Page: | E1976 |
| End Page: | E1987 |
| Language: | English |
| DOI: | 10.1210/jc.2013-3976 |
| PROVIDER: | scopus |
| PMCID: | PMC4184069 |
| PUBMED: | 25029414 |
| DOI/URL: | |
| Notes: | Export Date: 3 November 2014 -- Source: Scopus |
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