Monocarboxylate transporter dependent mechanism is involved in proliferation, migration, and invasion of human glioblastoma cell lines via activation of PI3K/Akt signaling pathway

PLoS One. 2024 Oct 30;19(10):e0312939. doi: 10.1371/journal.pone.0312939. eCollection 2024.

Abstract

Glioblastoma multiforme is one of the most common primary tumors of the central nervous system, with a very poor prognosis. Cancer cells have been observed to upregulate pH regulators, such as monocarboxylate transporters (MCTs), with an increase in MCT4 expression being observed in several malignancies. MCT4/ recombinant cluster of differentiation 147 (CD147) transporter complex was reported to stimulate vascular endothelial growth factor (VEGF) via the phosphatidylinositol 3 kinase (PI3K) /protein kinase B (Akt) pathway, which has been proven to mediate glioblastoma invasion and migration. The present study aimed to clarify the role of the MCT4/CD147 transporter complex in glioblastoma cell proliferation, migration, and invasion. In this work, lentiviral vectors were used to overexpress MCT4/CD147 and small interfering RNA (siRNA) was used to silence MCT4/CD147 in the human glioma cell lines U87 and U251, respectively. The effects on cell proliferation, migration and invasiveness, as well as the protein expression levels of MCT4 and CD147, extracellular lactate content and Akt activation were assessed by MTT, wound-healing and invasion assays, western blotting and colorimetric method, respectively. The analysis results suggested that cell proliferation, migration, invasion, and Akt activation were decreased by siRNA in all cell lines, but were increased by lentivirus-mediated MCT4 overexpression. These findings suggest that inhibiting the activity and expression of the MCT4/CD147 transporter complex via metabolic-targeting drugs, particularly in cells with a high rate of glycolysis, should be explored as a novel strategy for glioblastoma treatment.

MeSH terms

  • Basigin* / genetics
  • Basigin* / metabolism
  • Cell Line, Tumor
  • Cell Movement*
  • Cell Proliferation*
  • Glioblastoma* / genetics
  • Glioblastoma* / metabolism
  • Glioblastoma* / pathology
  • Humans
  • Monocarboxylic Acid Transporters* / genetics
  • Monocarboxylic Acid Transporters* / metabolism
  • Muscle Proteins* / genetics
  • Muscle Proteins* / metabolism
  • Neoplasm Invasiveness*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt* / metabolism
  • Signal Transduction*

Substances

  • Monocarboxylic Acid Transporters
  • Proto-Oncogene Proteins c-akt
  • Basigin
  • Muscle Proteins
  • SLC16A4 protein, human
  • Phosphatidylinositol 3-Kinases
  • BSG protein, human