Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment
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 s...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-05-01
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| Series: | Cell Reports Medicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666379120300197 |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Said Izreig Alexandra Gariepy Irem Kaymak Hannah R. Bridges Ariel O. Donayo Gaëlle Bridon Lisa M. DeCamp Susan M. Kitchen-Goosen Daina Avizonis Ryan D. Sheldon Rob C. Laister Mark D. Minden Nathalie A. Johnson Thomas F. Duchaine Marc S. Rudoltz Sanghee Yoo Michael N. Pollak Kelsey S. Williams Russell G. Jones |
| spellingShingle |
Said Izreig Alexandra Gariepy Irem Kaymak Hannah R. Bridges Ariel O. Donayo Gaëlle Bridon Lisa M. DeCamp Susan M. Kitchen-Goosen Daina Avizonis Ryan D. Sheldon Rob C. Laister Mark D. Minden Nathalie A. Johnson Thomas F. Duchaine Marc S. Rudoltz Sanghee Yoo Michael N. Pollak Kelsey S. Williams Russell G. Jones Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment Cell Reports Medicine biguanide microRNA LKB1 AMPK Myc lymphoma |
| author_facet |
Said Izreig Alexandra Gariepy Irem Kaymak Hannah R. Bridges Ariel O. Donayo Gaëlle Bridon Lisa M. DeCamp Susan M. Kitchen-Goosen Daina Avizonis Ryan D. Sheldon Rob C. Laister Mark D. Minden Nathalie A. Johnson Thomas F. Duchaine Marc S. Rudoltz Sanghee Yoo Michael N. Pollak Kelsey S. Williams Russell G. Jones |
| author_sort |
Said Izreig |
| title |
Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment |
| title_short |
Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment |
| title_full |
Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment |
| title_fullStr |
Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment |
| title_full_unstemmed |
Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment |
| title_sort |
repression of lkb1 by mir-17∼92 sensitizes myc-dependent lymphoma to biguanide treatment |
| publisher |
Elsevier |
| series |
Cell Reports Medicine |
| issn |
2666-3791 |
| publishDate |
2020-05-01 |
| description |
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. |
| topic |
biguanide microRNA LKB1 AMPK Myc lymphoma |
| url |
http://www.sciencedirect.com/science/article/pii/S2666379120300197 |
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doaj-d6a25ea75c0340f4b7b742c8469caad82020-11-25T04:09:05ZengElsevierCell Reports Medicine2666-37912020-05-0112100014Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide TreatmentSaid Izreig0Alexandra Gariepy1Irem Kaymak2Hannah R. Bridges3Ariel O. Donayo4Gaëlle Bridon5Lisa M. DeCamp6Susan M. Kitchen-Goosen7Daina Avizonis8Ryan D. Sheldon9Rob C. Laister10Mark D. Minden11Nathalie A. Johnson12Thomas F. Duchaine13Marc S. Rudoltz14Sanghee Yoo15Michael N. Pollak16Kelsey S. Williams17Russell G. Jones18Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, CanadaGoodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, CanadaMetabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USAMedical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UKGoodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, CanadaGoodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Metabolomics Core Facility, McGill University, Montreal, QC H3A 1A3, CanadaMetabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USAMetabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USAGoodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Metabolomics Core Facility, McGill University, Montreal, QC H3A 1A3, CanadaMetabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USAPrincess Margaret Cancer Centre, Department of Medical Oncology and Hematology, Toronto, ON M5G 2M9, CanadaPrincess Margaret Cancer Centre, Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, CanadaLady Davis Institute of the Jewish General Hospital and Department of Oncology, McGill University, Montreal, QC H3T 1E2, CanadaGoodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, CanadaImmunoMet Therapeutics, Houston, TX 77021, USAImmunoMet Therapeutics, Houston, TX 77021, USALady Davis Institute of the Jewish General Hospital and Department of Oncology, McGill University, Montreal, QC H3T 1E2, CanadaMetabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USAGoodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada; Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2666379120300197biguanidemicroRNALKB1AMPKMyclymphoma |