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

Abstract

One of the major metabolic changes associated with cellular transformation is enhanced nutrient utilization, which supports tumor progression by fueling both energy production and providing biosynthetic intermediates for growth. The liver kinase B1 (LKB1) is a serine/threonine kinase and tumor suppressor that couples bioenergetics to cell-growth control through regulation of mammalian target of rapamycin (mTOR) activity; however, the influence of LKB1 on tumor metabolism is not well defined. Here, we show that loss of LKB1 induces a progrowth metabolic program in proliferating cells. Cells lacking LKB1 display increased glucose and glutamine uptake and utilization, which support both cellular ATP levels and increased macromolecular biosynthesis. This LKB1-dependent reprogramming of cell metabolism is dependent on the hypoxia-inducible factor-1α (HIF-1α), which accumulates under normoxia in LKB1-deficient cells and is antagonized by inhibition of mTOR complex I signaling. Silencing HIF-1α reverses the metabolic advantages conferred by reduced LKB1 signaling and impairs the growth and survival of LKB1-deficient tumor cells under low-nutrient conditions. Together, our data implicate the tumor suppressor LKB1 as a central regulator of tumor metabolism and growth control through the regulation of HIF-1α-dependent metabolic reprogramming.HIF-1alpha | cancer metabolism | Warburg effect | Peutz-Jeghers Syndrome | PJS | glutamine metabolism A lthough unchecked cell proliferation and aberrant survival are hallmark features of cancer, tumor cells must also engage pathways of cellular metabolism to generate the energy and biosynthetic intermediates required to support increased cell division (1). To meet increased energetic and biosynthetic demand, cancer cells often display fundamental changes in their cellular metabolism, including a switch to aerobic glycolysis, a phenomenon known as the "Warburg effect" (2). Increased use of glutamine ("glutaminolysis") for mitochondrial-dependent ATP production and cellular biosynthesis is also a key feature of many tumor cells (3).Many of the predominant driver mutations observed in cancer alter tumor-cell metabolism as part of their mode of action (4). For example, loss of the tumor suppressor PTEN can promote increased glucose uptake through elevated PI3K/Akt/mTOR signaling (5) while loss of the Von-Hippel-Lindau (VHL) tumor suppressor promotes a similar metabolic phenotype through stabilization of the hypoxia inducible factor (HIF)-1α (6). HIF-1α and HIF-2α are transcription factors whose activity is regulated by oxygen availability. HIF-1α and HIF-2α protein expression is normally stabilized only under hypoxic conditions; however, the HIFs are commonly expressed in human cancers even in the absence of hypoxia (7). Importantly, elevated expression of both HIF-1α and HIF-2α has been demonstrated in many cases of non-small cell lung cancer (NSCLC) (8), and HIF-2α has been linked to poor prognosis in lung-cancer patients (9).The liver kinase B1 (LKB1) is a serine/threonine kinase enco...

Modulation of TORC2 Signaling by a Conserved Lkb1 Signaling Axis in Budding Yeast

“…During the delay, polar growth of the daughter bud continues, leading to growth of abnormally large cells. Loss of vertebrate Lkb1 also causes an increase in cell size (Faubert et al 2014). Furthermore, elm1∆ shows genetic interactions with G1 cyclins that suggest that it could function with Cln3, a G1 cyclin required for control of cell size in G1 phase (Sreenivasan et al 2003).…”

Metformin: a modulator of bevacizumab activity in cancer? A case report

“…In contrast, LKB1 was readily expressed in control tumors that were stained in parallel (not shown). Loss of LKB1 has also been shown to promote metabolic reprogramming in tumor cells by an HIF-1a-dependent mechanism, 13 suggesting that this might in part contribute to the highly glycolytic phenotype of liver metastasis.…”

Phe354Leu Polymorphism of LKB1 Is a Potential Prognostic Factor for Cytogenetically Normal Acute Myeloid Leukemia

“…In complex with two other proteins, the STe20-related adapter (STRAD) pseudokinase and the scaffolding protein mouse protein 25 (MO25) (10), LKB1 has been shown to regulate cell-cycle arrest, apoptosis, autophagia and cellular energy metabolism, as well as cell polarity (11)(12)(13)(14). LKB1 activates adenosine monophosphate (AMP)-activated protein kinase (AMPK) and other members of the AMPK family (15).…”