Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1α

TLDR

Liver kinase B1 (LKB1) is a serine/threonine kinase frequently inactivated in human cancers. Loss of LKB1 drives a pro‑growth metabolic reprogramming that enhances mTORC1 and ROS‑dependent HIF‑1α activity, rendering LKB1‑null cells dependent on HIF‑1α for ATP production under nutrient stress and indicating HIF‑1α as a potential synthetic lethal target.

Abstract

Significance Liver kinase B1 (LKB1) is a serine/threonine kinase often inactivated in human cancer. We demonstrate here that loss of LKB1 expression in cancer cells promotes a progrowth metabolic profile that enables increased cell growth and proliferation. Loss of LKB1 promotes increased tumor cell metabolism through mammalian target of rapamycin complex 1- and reactive oxygen species-dependent increases in hypoxia-inducible factor-1α (HIF-1α). LKB1-null cells are dependent on HIF-1α to maintain cellular ATP and viability under poor nutrient conditions, raising the possibility of targeting HIF-1α for synthetic lethality in LKB1-deficient tumors. Together, our data reveal that regulation of cellular metabolism is a key function of LKB1 that may contribute to its tumor-suppressor function in human cancer.