BACKGROUND: Because mammalian target of rapamycin (mTOR) may be involved in thyroid carcinogenesis, we investigated the expression and activation patterns of mTOR signaling proteins in thyroid carcinoma cells and tumors and their association with tumor histology and aggressiveness. METHODS: Tissue specimens from 50 patients with thyroid cancer were analyzed for eIF4E, a critical downstream target of the mTOR pathway, using immunohistochemistry. In addition, fresh-frozen samples from patients, and primary tumor cell cultures were analyzed for expression and activation of mTOR signaling proteins by Western blot. Moreover, pharmacologic studies with rapamycin were performed. RESULTS: High expression of eIF4E was observed in medullary thyroid carcinomas (MTC) and in aggressive variants of papillary thyroid carcinomas (PTC) as compared with conventional PTC and follicular thyroid carcinomas (P < .0001). The level of eIF4E expression also correlated with tumor stage (P = .002). Using Western blot analysis, p-rpS6, p-4EBP1, 4EBP1, and eIF4E were detected at higher levels in aggressive PTC and MTC cells. Treatment of MTC cells with increasing concentrations of rapamycin resulted in significant cell death and in decreased cell growth associated with deactivation of the mTOR pathway. CONCLUSION: mTOR signaling, which controls protein synthesis through regulation of translation initiation, is activated in aggressive PTC and MTC and represents a promising target for investigational therapies in these patients.
BACKGROUND: Because mammalian target of rapamycin (mTOR) may be involved in thyroid carcinogenesis, we investigated the expression and activation patterns of mTOR signaling proteins in thyroid carcinoma cells and tumors and their association with tumor histology and aggressiveness. METHODS: Tissue specimens from 50 patients with thyroid cancer were analyzed for eIF4E, a critical downstream target of the mTOR pathway, using immunohistochemistry. In addition, fresh-frozen samples from patients, and primary tumor cell cultures were analyzed for expression and activation of mTOR signaling proteins by Western blot. Moreover, pharmacologic studies with rapamycin were performed. RESULTS: High expression of eIF4E was observed in medullary thyroid carcinomas (MTC) and in aggressive variants of papillary thyroid carcinomas (PTC) as compared with conventional PTC and follicular thyroid carcinomas (P < .0001). The level of eIF4E expression also correlated with tumor stage (P = .002). Using Western blot analysis, p-rpS6, p-4EBP1, 4EBP1, and eIF4E were detected at higher levels in aggressive PTC and MTC cells. Treatment of MTC cells with increasing concentrations of rapamycin resulted in significant cell death and in decreased cell growth associated with deactivation of the mTOR pathway. CONCLUSION:mTOR signaling, which controls protein synthesis through regulation of translation initiation, is activated in aggressive PTC and MTC and represents a promising target for investigational therapies in these patients.
Authors: Abbas K Samadi; Joseph Bazzill; Xuan Zhang; Rob Gallagher; Hauping Zhang; Rao Gollapudi; Kelly Kindscher; Barbara Timmermann; Mark S Cohen Journal: Surgery Date: 2012-12 Impact factor: 3.982
Authors: J Musa; M F Orth; M Dallmayer; M Baldauf; C Pardo; B Rotblat; T Kirchner; G Leprivier; T G P Grünewald Journal: Oncogene Date: 2016-02-01 Impact factor: 9.867
Authors: Ira L Kraft; Srivandana Akshintala; John W Glod; Jack F Shern; Brigitte C Widemann; Yuelin Zhu; Haiyan Lei; Claudia Derse-Anthony; Eva Dombi; Seth M Steinberg; Maya Lodish; Steven G Waguespack; Oxana Kapustina; Elizabeth Fox; Frank M Balis; Maria J Merino; Paul S Meltzer Journal: Clin Cancer Res Date: 2017-11-29 Impact factor: 12.531