Repression of LKB1 by miR-17?92 Sensitizes MYC-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 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.

SUBMITTER: Izreig S 

PROVIDER: S-EPMC7249503 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature