GANT61 elevates chemosensitivity to cisplatin through regulating the Hedgehog, AMPK and cAMP pathways in ovarian cancer

Future Med Chem. 2022 Apr;14(7):479-500. doi: 10.4155/fmc-2021-0310. Epub 2022 Mar 24.

Abstract

Background: This study aimed to explore the effect of GANT61 on ovarian cancer (OC) chemosensitivity. Materials & methods: OC cells (Caov-3 and SKOV-3) were treated by GANT61 alone or combined with cisplatin/taxol. The mRNA sequencing was conducted, followed by rescue experiments. Results: GANT61 reduced OC cell viability in a dose-dependent manner and enhanced chemosensitivity to cisplatin but not to taxol. In total, 545 dysregulated genes were identified after the addition of GANT61 to cisplatin-treated OC cells, which were enriched in the AMPK, Hedgehog and cAMP pathways, then further validated by western blot. Furthermore, rescue experiments observed that AMPK pathway inhibitor and cAMP pathway inhibitor attenuated GANT61's chemosensitivity to cisplatin. Conclusion: GANT61 enforces OC chemosensitivity to cisplatin by regulating the Hedgehog, AMPK and cAMP pathways.

Keywords: AMPK signaling pathway; GANT61; Hedgehog signaling pathway; cAMP signaling pathway; cisplatin; ovarian cancer.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Cell Line, Tumor
  • Cisplatin* / pharmacology
  • Cyclic AMP / metabolism
  • Female
  • Hedgehog Proteins / metabolism
  • Humans
  • Ovarian Neoplasms* / drug therapy
  • Pyridines* / pharmacology
  • Pyrimidines* / pharmacology
  • Signal Transduction

Substances

  • GANT 61
  • Hedgehog Proteins
  • Pyridines
  • Pyrimidines
  • Cyclic AMP
  • AMP-Activated Protein Kinases
  • Cisplatin