PMID- 22389381 OWN - NLM STAT- MEDLINE DCOM- 20120907 LR - 20211203 IS - 1479-6821 (Electronic) IS - 1351-0088 (Linking) VI - 19 IP - 3 DP - 2012 Jun TI - Metformin inhibits growth and decreases resistance to anoikis in medullary thyroid cancer cells. PG - 447-56 LID - 10.1530/ERC-12-0046 [doi] AB - Medullary thyroid cancer (MTC) is associated with activation of mammalian target of rapamycin (mTOR) signaling pathways. Recent studies showed that the antidiabetic agent metformin decreases proliferation of cancer cells through 5'-AMP-activated protein kinase (AMPK)-dependent inhibition of mTOR. In the current study, we assessed the effect of metformin on MTC cells. For this purpose, we determined growth, viability, migration, and resistance to anoikis assays using two MTC-derived cell lines (TT and MZ-CRC-1). Expressions of molecular targets of metformin were examined in MTC cell lines and in 14 human MTC tissue samples. We found that metformin inhibited growth and decreased expression of cyclin D1 in MTC cells. Treatment with metformin was associated with inhibition of mTOR/p70S6K/pS6 signaling and downregulation of pERK in both TT and MZ-CRC-1 cells. Metformin had no significant effects on pAKT in the cell lines examined. Metformin-inducible AMPK activation was noted only in TT cells. Treatment with AMPK inhibitor (compound C) or AMPK silencing did not prevent growth inhibitory effects of metformin in TT cells. Metformin had no effect on MTC cell migration but reduced the ability of cells to form multicellular spheroids in nonadherent conditions. Immunostaining of human MTC showed over-expression of cyclin D1 in all tumors compared with corresponding normal tissue. Activation of mTOR/p70S6K was detected in 8/14 (57.1%) examined tumors. Together, these findings indicate that growth inhibitory effects in MTC cells are associated with downregulation of both mTOR/6SK and pERK signaling pathways. Expression of metformin's molecular targets in human MTC cells suggests its potential utility for the treatment of MTC in patients. FAU - Klubo-Gwiezdzinska, Joanna AU - Klubo-Gwiezdzinska J AD - Department of Pediatrics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USA. FAU - Jensen, Kirk AU - Jensen K FAU - Costello, John AU - Costello J FAU - Patel, Aneeta AU - Patel A FAU - Hoperia, Victoria AU - Hoperia V FAU - Bauer, Andrew AU - Bauer A FAU - Burman, Kenneth D AU - Burman KD FAU - Wartofsky, Leonard AU - Wartofsky L FAU - Vasko, Vasyl AU - Vasko V LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120524 PL - England TA - Endocr Relat Cancer JT - Endocrine-related cancer JID - 9436481 RN - 0 (Antineoplastic Agents) RN - 0 (Protein Kinase Inhibitors) RN - 9100L32L2N (Metformin) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases) RN - Thyroid cancer, medullary SB - IM MH - AMP-Activated Protein Kinase Kinases MH - Anoikis/drug effects MH - Antineoplastic Agents/*pharmacology MH - Carcinoma, Neuroendocrine MH - Cell Line, Tumor MH - Cell Movement/drug effects MH - Cell Proliferation/drug effects MH - Humans MH - Metformin/*pharmacology MH - Mitogen-Activated Protein Kinases/metabolism MH - Protein Kinase Inhibitors/*pharmacology MH - Protein Kinases/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Ribosomal Protein S6 Kinases/metabolism MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism MH - Thyroid Neoplasms/*drug therapy/metabolism/pathology EDAT- 2012/03/06 06:00 MHDA- 2012/09/08 06:00 CRDT- 2012/03/06 06:00 PHST- 2012/03/06 06:00 [entrez] PHST- 2012/03/06 06:00 [pubmed] PHST- 2012/09/08 06:00 [medline] AID - ERC-12-0046 [pii] AID - 10.1530/ERC-12-0046 [doi] PST - epublish SO - Endocr Relat Cancer. 2012 May 24;19(3):447-56. doi: 10.1530/ERC-12-0046. Print 2012 Jun.