Repression of LKB1 by <i>miR-17∼92</i> Sensitizes <i>MYC</i>-Dependent Lymphoma to Biguanide Treatment.

Abstract

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 <i>miR-17∼92</i> expression in <i>Myc</i>^<i>+</i> lymphoma cells promotes increased apoptosis to biguanide treatment <i>in vitro</i> and <i>in vivo</i>. This effect is driven by the <i>miR-17</i>-dependent silencing of LKB1, which reduces AMPK activation in response to complex I inhibition. Mechanistically, biguanide treatment induces metabolic stress in <i>Myc</i>^<i>+</i> lymphoma cells by inhibiting TCA cycle metabolism and mitochondrial respiration, exposing metabolic vulnerability. Finally, we demonstrate a direct correlation between <i>miR-17∼92</i> expression and biguanide sensitivity in human cancer cells. Our results identify <i>miR-17∼92</i> expression as a potential biomarker for biguanide sensitivity in malignancies.