The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress

TLDR

AMP‑activated protein kinase (AMPK) is a conserved cellular energy sensor activated by increased AMP/ATP ratio and requires phosphorylation at Thr‑172 by an upstream kinase, the identity of which in mammals has been unclear. The study proposes a model explaining how LKB1, a tumor suppressor, can sensitize cells to energy‑stress‑induced apoptosis while resisting oncogene‑driven transformation. LKB1 directly phosphorylates AMPKα at Thr‑172 to activate its kinase activity, and loss of LKB1 abolishes this phosphorylation and downstream signaling, while reintroduction of wild‑type but not kinase‑dead LKB1 restores AMPK activity. LKB1 is the dominant regulator of AMPK activation, and its loss makes cells hypersensitive to energy‑stress‑induced apoptosis, indicating that targeting the LKB1/AMPK pathway could provide therapeutic opportunities in certain cancers.

Abstract

AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status found in all eukaryotic cells. AMPK is activated by stimuli that increase the cellular AMP/ATP ratio. Essential to activation of AMPK is its phosphorylation at Thr-172 by an upstream kinase, AMPKK, whose identity in mammalian cells has remained elusive. Here we present biochemical and genetic evidence indicating that the LKB1 serine/threonine kinase, the gene inactivated in the Peutz-Jeghers familial cancer syndrome, is the dominant regulator of AMPK activation in several mammalian cell types. We show that LKB1 directly phosphorylates Thr-172 of AMPKα in vitro and activates its kinase activity. LKB1-deficient murine embryonic fibroblasts show nearly complete loss of Thr-172 phosphorylation and downstream AMPK signaling in response to a variety of stimuli that activate AMPK. Reintroduction of WT, but not kinase-dead, LKB1 into these cells restores AMPK activity. Furthermore, we show that LKB1 plays a biologically significant role in this pathway, because LKB1-deficient cells are hypersensitive to apoptosis induced by energy stress. On the basis of these results, we propose a model to explain the apparent paradox that LKB1 is a tumor suppressor, yet cells lacking LKB1 are resistant to cell transformation by conventional oncogenes and are sensitive to killing in response to agents that elevate AMP. The role of LKB1/AMPK in the survival of a subset of genetically defined tumor cells may provide opportunities for cancer therapeutics.