Inhibition of PI3K/mTOR increased the sensitivity of hepatocellular carcinoma cells to cisplatin via interference with mitochondrial-lysosomal crosstalk

Cell Prolif. 2019 May;52(3):e12609. doi: 10.1111/cpr.12609. Epub 2019 Apr 29.

Abstract

Objectives: The genotoxicity of cisplatin towards nuclear DNA is not sufficient to explain the cisplatin resistance of hepatocellular carcinoma (HCC) cells; cisplatin interacts with many organelles, which can influence the sensitivity. Here, we explored the role of mitochondrial-lysosomal crosstalk in the cisplatin resistance of HCC cells.

Materials and methods: Huh7 and HepG2 cells were subjected to different treatments. Flow cytometry was conducted to detect mitochondrial reactive oxygen species, mitochondrial mass, lysosomal function, mitochondrial membrane potential and apoptosis. Western blotting was performed to evaluate protein levels. The oxygen consumption rate was measured to evaluate mitochondrial function.

Results: Cisplatin activated mitophagy and lysosomal biogenesis, resulting in crosstalk between mitochondria and lysosomes and cisplatin resistance in HCC cells. Furthermore, a combination of cisplatin with the phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor PKI-402 induced lysosomal membrane permeabilization. This effect changed the role of the lysosome from a protective one to that of a cell death promoter, completely destroying the mitochondrial-lysosomal crosstalk and significantly enhancing the sensitivity of HCC cells to cisplatin.

Conclusions: This is the first evidence of the importance of mitochondrial-lysosomal crosstalk in the cisplatin resistance of HCC cells and of the destruction of this crosstalk by a PI3K/mTOR inhibitor to increase the sensitivity of HCC cells to cisplatin. This mechanism could be developed as a novel target for treatment of HCC in the future.

Keywords: chemotherapy resistance; hepatocellular carcinoma; lysosomal biogenesis; mitochondrial-lysosomal crosstalk; mitophagy.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism*
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondrial Dynamics / drug effects
  • Mitophagy / drug effects
  • Phenylurea Compounds / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Pyrimidines / pharmacology
  • Reactive Oxygen Species / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • PKI 402
  • Phenylurea Compounds
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyrimidines
  • Reactive Oxygen Species
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Cisplatin