Flotillin-1 promotes progression and dampens chemosensitivity to cisplatin in gastric cancer via ERK and AKT signaling pathways

Eur J Pharmacol. 2022 Feb 5:916:174631. doi: 10.1016/j.ejphar.2021.174631. Epub 2021 Nov 12.

Abstract

Background: Several past studies have reported the overexpression of Flotillin-1 in a variety of cancer types. Cisplatin is a chemotherapeutic drug commonly used for cancer treatment. The present study investigated the role of Flotillin-1 in the progression of GC and assessed whether it assists in the chemical sensitization of GC cells toward cisplatin.

Method: The expression of Flotillin-1 was detected both in human gastric mucosal cells and GC cells. Next, siRNA and shRNA were used to construct a stable cell line expressing low levels of Flotillin-1. Furthermore, the Cell Counting Kit 8 (CCK-8), flow cytometry, and transwell assays were employed to detect the impact of Flotillin-1 on GC cells. In addition, a nude mouse model of human GC was used to verify the knockdown of Flotillin-1 to increase the sensitivity of GC cells to cisplatin.

Results: Flotillin-1 was overexpressed in GC cells when compared to that in human gastric mucosal cells. The results for in vitro and vivo assays revealed that the knockdown of Flotillin-1 could significantly inhibit the proliferation of GC cells and increased the sensitivity of GC cells to cisplatin via the regulation of the protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) signaling pathway.

Conclusion: Flotillin-1 might be used as a molecular marker for GC diagnosis and could be explored as a potential new target for the treatment of GC.

Keywords: Chemosensitivity; Cisplatin; Flotillin-1; GC.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Cisplatin / pharmacology*
  • Cisplatin / therapeutic use
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Nude
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology
  • Up-Regulation

Substances

  • Antineoplastic Agents
  • Membrane Proteins
  • flotillins
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Cisplatin