title: A novel dual AMPK activator/mTOR inhibitor inhibits thyroid cancer cell growth.
abstract: BACKGROUND
  Activated AMP protein kinase (AMPK) is a key regulator of intracellular energy homeostasis and may also function as a tumor suppressor by inhibiting cell growth through suppression of mammalian target of rapamycin (mTOR)/p70S6K signaling. AMPK activating agents, such as metformin and 5-aminoimidazole-4-carboxamide-ribonucleoside, have been demonstrated to inhibit thyroid cancer cell growth in in vitro and in vivo models. OSU-53, a recently developed AMPK activator, was previously shown to exhibit both in vitro and in vivo antitumor activity against aggressive breast cancer cell lines and their xenografts in nude mice.
  
  
  OBJECTIVE
  The objective of the study was to assess the in vitro effects of OSU-53 treatment in a panel of thyroid cancer cells.
  
  
  METHODS
  Experiments were performed to determine the effects of OSU-53 on cell growth, oncogenic signaling, apoptosis, autophagy, and cell rescue after selective knockdown of AMPK.
  
  
  RESULTS
  OSU-53 inhibited in vitro cell growth of all seven thyroid cancer cells tested and induced activation of AMPK. Cell lines with activating mutations in RAS or BRAF, compared with cells with phosphatase and tensin homolog deleted from chromosome 10 null and RET/papillary thyroid carcinoma mutations, were more sensitive to drug treatment and demonstrated a more robust AMPK activation, inhibition of mTOR signaling, and autophagy stimulation. After selective knockdown of AMPK, cell rescue from OSU-53 treatment was not observed. We demonstrated an off-target effect of direct mTOR inhibition by OSU-53. Increased autophagy was observed in cells with activation RAS or BRAF mutations.
  
  
  CONCLUSIONS
  OSU-53, a novel dual-AMPK activator/mTOR inhibitor, effectively inhibits growth in a variety of thyroid cancer cell lines and is most potent in cells with activating mutations in RAS or BRAF.
authors.affiliation: Division of Surgical Oncology (R.L.P., J.E.P.), Department of Surgery, Division of Endocrinology, Diabetes, and Metabolism (A.M.Y., C.W., M.S., M.D.R.), Department of Medicine, The Ohio State University, Arthur G. James Comprehensive Cancer Center, and Richard G. Solove Research Institute, and Division of Medicinal Chemistry (C.-S.C.), College of Pharmacy, Columbus, Ohio 43210; and Center for Biostatistics (X.Z.), The Ohio State University, Columbus, Ohio 43221.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Plews
authors.forename: Adlina
authors.initials: A
authors.lastname: Mohd Yusof
authors.forename: Chaojie
authors.initials: C
authors.lastname: Wang
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Saji
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ringel
authors.forename: John E
authors.initials: JE
authors.lastname: Phay
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: C000599963:OSU-53; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D045162:Thiazolidinediones; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases