Robert L Plews1, Adlina Mohd Yusof, Chaojie Wang, Motoyasu Saji, Xiaoli Zhang, Ching-Shih Chen, Matthew D Ringel, John E Phay. 1. 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.
Abstract
CONTEXT: 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. DESIGN: 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.
CONTEXT: 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. DESIGN: 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: Roberta Malaguarnera; Kuen-Yuan Chen; Tae-Yong Kim; Jose M Dominguez; Francesca Voza; Bin Ouyang; Sushil K Vundavalli; Jeffrey A Knauf; James A Fagin Journal: J Clin Endocrinol Metab Date: 2014-07-16 Impact factor: 5.958
Authors: M D Ringel; N Hayre; J Saito; B Saunier; F Schuppert; H Burch; V Bernet; K D Burman; L D Kohn; M Saji Journal: Cancer Res Date: 2001-08-15 Impact factor: 12.701
Authors: Alexandra Faustino; Joana P Couto; Helena Pópulo; Ana Sofia Rocha; Fernando Pardal; José Manuel Cameselle-Teijeiro; José Manuel Lopes; Manuel Sobrinho-Simões; Paula Soares Journal: J Clin Endocrinol Metab Date: 2012-05-01 Impact factor: 5.958
Authors: Chaojie Wang; Motoyasu Saji; Steven E Justiniano; Adlina Mohd Yusof; Xiaoli Zhang; Lianbo Yu; Soledad Fernández; Paul Wakely; Krista La Perle; Hiroshi Nakanishi; Neal Pohlman; Matthew D Ringel Journal: JCI Insight Date: 2017-03-09
Authors: Prashant Trikha; Robert L Plews; Andrew Stiff; Shalini Gautam; Vincent Hsu; David Abood; Robert Wesolowski; Ian Landi; Xiaokui Mo; John Phay; Ching-Shih Chen; John Byrd; Michael Caligiuri; Susheela Tridandapani; William Carson Journal: Oncoimmunology Date: 2016-07-25 Impact factor: 8.110