Purpose Mitochondrial glycerophosphate dehydrogenase (mGPDH) is the key enzyme connecting oxidative phosphorylation (OXPHOS) and glycolysis as well as a target of the antidiabetic drug metformin (MF) in the liver. There are no data on the expression and role of mGPDH as a metformin target in cancer. In this study, we evaluated mGPDH as a potential target of metformin in thyroid cancer and investigated its contribution in thyroid cancer metabolism. Experimental design We analyzed mGPDH expression in 253 thyroid cancer and normal tissues by immunostaining and examined its expression and localization in thyroid cancer-derived cell lines (FTC133, BCPAP) by confocal microscopy. The effects of metformin on mGPDH expression were determined by qRT-PCR and western blot. Seahorse analyzer was utilized to assess the effects of metformin on OXPHOS and glycolysis in thyroid cancer cells. We analyzed the effects of metformin on tumor growth and mGPDH expression in metastatic thyroid cancer mouse models. Results We show for the first time that mGPDH is overexpressed in thyroid cancer compared with normal thyroid. We demonstrate that mGPDH regulates human thyroid cancer cell growth and OXPHOS rate in vitro. Metformin treatment is associated with downregulation of mGPDH expression and inhibition of OXPHOS in thyroid cancer in vitro. Cells characterized by high mGPDH expression are more sensitive to OXPHOS-inhibitory effects of metformin in vitro and growth inhibitory effects of metformin in vitro and in vivo. Conclusion Our study established mGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin.

Incidence of endocrine cancers is rising every year. Over the last decade, evidence has accumulated that demonstrates the anti-cancer effects of an anti-diabetic drug, metformin, in endocrine malignancies. We performed a literature review utilizing the PubMed, Medline and clinicaltrials.gov databases using the keyword ‘metformin’ plus the following terms: ‘thyroid cancer’, ‘thyroid nodules’, ‘parathyroid’, ‘hyperparathyroidism’, ‘adrenal adenoma’, ‘Cushing syndrome’, ‘hyperaldosteronism’, ‘adrenocortical cancer’, ‘neuroendocrine tumor (NET)’, ‘pancreatic NET (pNET)’, ‘carcinoid’, ‘pituitary adenoma’, ‘pituitary neuroendocrine tumor (PitNET)’, ‘prolactinoma’, ‘pheochromocytoma/paraganglioma’. We found 37 studies describing the preclinical and clinical role of metformin in endocrine tumors. The available epidemiological data show an association between exposure of metformin and lower incidence of thyroid cancer and pNETs in diabetic patients. Metformin treatment has been associated with better response to cancer therapy in thyroid cancer and pNETs. Preclinical evidence suggests that the primary direct mechanisms of metformin action include inhibition of mitochondrial oxidative phosphorylation via inhibition of both mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase, leading to metabolic stress. Decreased ATP production leads to an activation of a cellular energy sensor, AMPK, and subsequent downregulation of mTOR signaling pathway, which is associated with decreased cellular proliferation. We also describe several AMPK-independent mechanisms of metformin action, as well as the indirect mechanisms targeting insulin resistance. Overall, repositioning of metformin has emerged as a promising strategy for adjuvant therapy of endocrine tumors. The mechanisms of synergy between metformin and other anti-cancer agents need to be elucidated further to guide well-designed prospective trials on combination therapies in endocrine malignancies.

We demonstrated that somatostatin receptor type 2 (SSTR2) may serve as a molecular target in the diagnosis and treatment of a subset of thyroid cancer (TC) patients. We showed that TC lesions have higher SSTR2 expression than normal thyroid. Further, we reported high uptake of SST analog 68 Ga-DOTA-TATE in a subset of TC patients, particularly in Hurthle-cell TC resistant to standard treatment. In vivo studies demonstrated that the theranostic efficacy of SST analogs could be enhanced by utilizing radiolabeled DOTA-EB-TATE, which is characterized by significantly higher tumor uptake than DOTA-TATE and DOTA-JR11. Treatment with 177 Lu-DOTA-EB-TATE extended survival and reduced tumor size in a mouse model with high-SST analog uptake, comparable with the uptake observed in human Hurthle-cell TC. Overall, 177 Lu-DOTA-EB-TATE has the potential to be translated from bench to bedside for the targeted therapy of TC patients characterized by high tumor uptake of SST analogs.

Key Points Question Is thyrotropin suppression associated with better outcomes in patients with intermediate- and high-risk differentiated thyroid cancer? Findings In this cohort study including 867 patients with intermediate- and high-risk differentiated thyroid cancer followed up for a mean (SD) of 7.2 (5.8) years, thyrotropin suppression was not associated with improved progression-free survival or overall survival. Meaning Patients with intermediate- and high-risk differentiated thyroid cancer might not benefit from thyrotropin suppression.