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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.

SUBMITTER: Faubert B

PROVIDER: S-EPMC3932920 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We focus on investigating the role of Parthenolide (Par), a small sesquiterpenoid molecule, in hepatocellular carcinoma (HCC) and its effective target.Highly-metastatic HCC cells, MHCC97-H, were divided into the DMSO and the Par groups, of which the Par group was intervened at 5 and 10 mg/L doses. Cell viability was assessed by CCK-8 assay. Transwell chamber assay was performed to examine the metastatic and invasive abilities, while plate clone formation assay was conducted to detect the clone formation ability. For analysis of glucose uptake, glycolytic ability and lactate level, the glycolysis assay was employed. Brdu staining was performed to evaluate the cell proliferative potential. The P50 and HIF-1α levels were measured by immunofluorescence, while the expressions of p-P50 and HIF-1α were determined by Western-Blot. Small molecule-protein docking and Pull-down experiments were conducted to validate the Par-P50 binding model. After establishing the tumor-bearing mouse model, Par was administered by gavage to measure the tissue levels of P50 and HIF-1α, followed by plotting of tumor growth curves.Par could inhibit the metastatic, invasive and clone formation abilities of MHCC97-H cells, reduce the cell proliferative potential, and suppress the glycolysis, as manifested by down-regulated level of lactate and reduced oxygen consumption. Meanwhile, Par inhibited the HIF-1α expression. We found that after silencing P50, the HIF-1α was down-regulated, the glycolytic ability decreased drastically, and the cellular metastatic and invasive abilities were suppressed. After P50 knockout, the effect of Par intervention on the MHCC97-H cells was reduced. In HCC-bearing mice, Par also exhibited an excellent anti-tumor effect, decreasing the tissue levels of P50 and HIF-1α.This study discovers that Par can inhibit the HIF-1α-mediated glycolysis of HCC cells by targeting P50, thereby exerting an anti-tumor effect. P50 is a major effective target of Par.

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

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