Dataset Information

Translational and HIF-1?-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides.

ABSTRACT: There is increasing interest in therapeutically exploiting metabolic differences between normal and cancer cells. We show that kinase inhibitors (KIs) and biguanides synergistically and selectively target a variety of cancer cells. Synthesis of non-essential amino acids (NEAAs) aspartate, asparagine, and serine, as well as glutamine metabolism, are major determinants of the efficacy of KI/biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine, and serine synthesis by modulating mRNA translation, while ablation of 4E-BP1/2 substantially decreases sensitivity of breast cancer and melanoma cells to KI/biguanide combinations. Efficacy of the KI/biguanide combinations is also determined by HIF-1?-dependent perturbations in glutamine metabolism, which were observed in VHL-deficient renal cancer cells. This suggests that cancer cells display metabolic plasticity by engaging non-redundant adaptive mechanisms, which allows them to survive therapeutic insults that target cancer metabolism.

SUBMITTER: Hulea L

PROVIDER: S-EPMC7252493 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

Translational and HIF-1α-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides.

Hulea Laura L Gravel Simon-Pierre SP Morita Masahiro M Cargnello Marie M Uchenunu Oro O Im Young Kyuen YK Lehuédé Camille C Ma Eric H EH Leibovitch Matthew M McLaughlan Shannon S Blouin Marie-José MJ Parisotto Maxime M Papavasiliou Vasilios V Lavoie Cynthia C Larsson Ola O Ohh Michael M Ferreira Tiago T Greenwood Celia C Bridon Gaëlle G Avizonis Daina D Ferbeyre Gerardo G Siegel Peter P Jones Russell G RG Muller William W Ursini-Siegel Josie J St-Pierre Julie J Pollak Michael M Topisirovic Ivan I

Cell metabolism 20180920 6

There is increasing interest in therapeutically exploiting metabolic differences between normal and cancer cells. We show that kinase inhibitors (KIs) and biguanides synergistically and selectively target a variety of cancer cells. Synthesis of non-essential amino acids (NEAAs) aspartate, asparagine, and serine, as well as glutamine metabolism, are major determinants of the efficacy of KI/biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine, and serine synthesis by modul ...[more]

PMID: 30244971

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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.

Dataset Information

Translational and HIF-1?-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides.

Publications

Translational and HIF-1α-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides.

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