Profiling and targeting of cellular mitochondrial bioenergetics: inhibition of human gastric cancer cell growth by carnosine

Acta Pharmacol Sin. 2019 Jul;40(7):938-948. doi: 10.1038/s41401-018-0182-8. Epub 2018 Dec 18.

Abstract

L-Carnosine (β-alanyl-L-histidine) is a naturally occurring dipeptide distributed in various organs of mammalians. We previously showed that carnosine inhibited proliferation of human gastric cancer cells through targeting both mitochondrial bioenergetics and glycolysis pathway. But the mechanism underlying carnosine action on mitochondrial bioenergetics of tumor cells remains unclear. In the current study we investigated the effect of carnosine on the growth of human gastric cancer SGC-7901 cells in vitro and in vivo. We firstly showed that hydrolysis of carnosine was not a prerequisite for its anti-gastric cancer effect. Treatment of SGC-7901 cells with carnosine (20 mmol/L) significantly decreased the activities of mitochondrial respiratory chain complexes I-IV and mitochondrial ATP production, and downregulated 13 proteins involved in mitochondrial bioenergetics. Furthermore, carnosine treatment significantly suppressed the phosphorylation of Akt, while inhibition of Akt activation with GSK690693 significantly reduced the localization of prohibitin-1 (PHB-1) in the mitochondria of SGC-7901 and BGC-823 cells. In addition, we showed that silencing of PHB-1 gene with shRNA markedly reduced the mitochondrial PHB-1 in SGC-7901 cells, and significantly decreased the colony formation capacity and growth rate of the cells. In SGC-7901 cell xenograft nude mice, administration of carnosine (250 mg kg/d, ip, for 3 weeks) significantly inhibited the tumor growth and decreased the expression of mitochondrial PHB-1 in tumor tissue. Taken together, these results suggest that carnosine may act on multiple mitochondrial proteins to down-regulate mitochondrial bioenergetics and then to inhibit the growth and proliferation of SGC-7901 and BGC-823 cells.

Keywords: Akt; carnosine; human gastric cancer cells; mitochondrial bioenergetics; prohibitin-1 (PHB-1).

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Carnosine / pharmacology
  • Carnosine / therapeutic use*
  • Cell Line, Tumor
  • Electron Transport Chain Complex Proteins / metabolism
  • Energy Metabolism / drug effects*
  • Female
  • Humans
  • Mice, Nude
  • Mitochondria / drug effects*
  • Mitochondrial Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Repressor Proteins / metabolism
  • Stomach Neoplasms / drug therapy*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Electron Transport Chain Complex Proteins
  • Mitochondrial Proteins
  • Repressor Proteins
  • prohibitin
  • Carnosine
  • Proto-Oncogene Proteins c-akt