Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment

Cell Reports Medicine

Susan M. Kitchen-Goosen¹  Alexandra Gariepy²  Hannah R. Bridges²  Ryan D. Sheldon³  Thomas F. Duchaine³  Nathalie A. Johnson⁴  Lisa M. DeCamp⁴  Russell G. Jones⁴  Daina Avizonis⁴  Said Izreig⁴  Irem Kaymak⁴  Kelsey S. Williams⁵  Gaëlle Bridon⁶  Mark D. Minden⁷  Rob C. Laister⁷  Marc S. Rudoltz⁷  Ariel O. Donayo⁷  Michael N. Pollak⁸  Sanghee Yoo⁹ 

[1] Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada;Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada;Metabolomics Core Facility, McGill University, Montreal, QC H3A 1A3, Canada;Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada;Lady Davis Institute of the Jewish General Hospital and Department of Oncology, McGill University, Montreal, QC H3T 1E2, Canada;Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK;Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USA;Princess Margaret Cancer Centre, Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada;Princess Margaret Cancer Centre, Department of Medical Oncology and Hematology, Toronto, ON M5G 2M9, Canada;

关键词: biguanide;    microRNA;    LKB1;    AMPK;    Myc;    lymphoma;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: Cancer cells display metabolic plasticity to survive stresses in the tumor microenvironment. Cellular adaptation to energetic stress is coordinated in part by signaling through the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Here, we demonstrate that miRNA-mediated silencing of LKB1 confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and newly developed (IM156) biguanides, we demonstrate that elevated miR-17∼92 expression in Myc+ lymphoma cells promotes increased apoptosis to biguanide treatment in vitro and in vivo. This effect is driven by the miR-17-dependent silencing of LKB1, which reduces AMPK activation in response to complex I inhibition. Mechanistically, biguanide treatment induces metabolic stress in Myc+ lymphoma cells by inhibiting TCA cycle metabolism and mitochondrial respiration, exposing metabolic vulnerability. Finally, we demonstrate a direct correlation between miR-17∼92 expression and biguanide sensitivity in human cancer cells. Our results identify miR-17∼92 expression as a potential biomarker for biguanide sensitivity in malignancies.

【 授权许可】

Unknown