Arginine ADP-ribosyltransferase 1 Regulates Glycolysis in Colorectal Cancer via the PI3K/AKT/HIF1α Pathway

Curr Med Sci. 2022 Aug;42(4):733-741. doi: 10.1007/s11596-022-2606-4. Epub 2022 Jul 7.

Abstract

Objective: Arginine ADP-ribosyltransferase 1 (ART1) is involved in the regulation of a diverse array of pathophysiological processes, including proliferation, invasion, apoptosis, autophagy and angiogenesis of colorectal cancer (CRC) cells. However, how ART1 regulates glycolysis in CRC remains elusive.

Methods: To elucidate the role of ART1 in glycolysis in CRC, we assessed the protein level of ART1, hypoxia-inducible factor 1α (HIF1α), and glucose transporter type 1 (GLUT1) in 61 CRC tumor tissue specimens obtained from patients with different 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) uptake as analyzed by PET/CT before surgery. Colon adenocarcinoma CT26 cells with ART1 knockdown and overexpression were established, respectively, and the molecular mechanism underlying the effect of ART1 on glycolysis in CRC was determined both in vivo and in vitro.

Results: The expression of ART1 and GLUT1 was significantly associated with FDG uptake (P=0.037 and P=0.022, respectively) in CRC tissues. Furthermore, the expression of hexokinase 2 (HK2) and lactate dehydrogenase (LDH) was upregulated in ART1-overexpressed CT26 cells, but was downregulated in ART1-knockdown CT26 cells. The volume and weight of subcutaneously transplanted tumors were markedly increased in the ART1-overexpressed BALB/c mice group and decreased in the ART1-knockdown group. In CT26 cells, the overexpression of ART1 promoted the expression levels of HK2 and LDH, and knockdown of ART1 suppressed them in the CT26 tumors. In both normal and hypoxic conditions, ART1 expression was associated with the protein level of phospho-serine/threonine kinase (p-AKT), HIF1α, and GLUT1 but not with that of AKT in CT26 cells and subcutaneous transplanted tumors.

Conclusion: ART1 plays a crucial role in the elevation of glucose consumption in CT26 cells and may regulate GLUT1-dependent glycolysis in CRC via the PI3K/AKT/HIF1α pathway.

Keywords: Warburg effect; arginine ADP-ribosyltransferases 1; colorectal cancer; glucose transporter type 1; hypoxia-inducible factor.

MeSH terms

  • ADP Ribose Transferases / metabolism
  • Adenocarcinoma*
  • Animals
  • Arginine / metabolism
  • Cell Line, Tumor
  • Colonic Neoplasms*
  • Fluorodeoxyglucose F18
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 1 / metabolism
  • Glycolysis
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mice
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Positron Emission Tomography Computed Tomography
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism

Substances

  • Glucose Transporter Type 1
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Fluorodeoxyglucose F18
  • Arginine
  • ADP Ribose Transferases
  • Proto-Oncogene Proteins c-akt