Leptin activates Akt in oesophageal cancer cells via multiple atorvastatin-sensitive small GTPases. Academic Article uri icon

Overview

abstract

  • Obesity is a risk factor for Barrett's oesophagus and oesophageal adenocarcinoma. Adipose tissue secretes the hormone leptin. Leptin is a growth factor for several cell types, including Barrett's cells and oesophageal adenocarcinoma cells. Statins are associated with reduced rates of Barrett's oesophagus and oesophageal cancer and exhibit anti-cancer effects in vitro. The mechanisms of these effects are not fully established. We have examined the effects of leptin and the lipid-soluble statin, atorvastatin, on signalling via monomeric GTP-binding proteins and Akt. Proliferation and apoptosis were assessed in OE33 cells. Akt activity was quantified by cell-based ELISA and in vitro kinase assay. Specific small-molecule inhibitors and a dominant-negative construct were used to reduce Akt activity. Small GTPases were inhibited using transfection of dominant-negative plasmids, prenylation inhibitors and pretreatment with atorvastatin. Leptin stimulated Akt activity and cell proliferation and inhibited camptothecin-induced apoptosis in an Akt-sensitive manner. Leptin induced phosphorylation of Bad and FOXO1 in an Akt-sensitive manner. Leptin activated Ras, Rac, RhoA and cdc42. Transfection of dominant-negative plasmids confirmed that leptin-induced Akt activation required Ras, RhoA cdc42 but not Rac. Atorvastatin inhibited leptin-induced activation of Ras, RhoA, cdc42 and Akt. Co-treatment with mevalonate prevented these effects of atorvastatin. The protein kinase Akt is essential to the growth-promoting and anti-apoptotic effects of leptin in oesophageal adenocarcinoma cells. Akt is activated via Ras-, Rho- and cdc42-dependant pathways. Atorvastatin reduces leptin-induced Akt activation by inhibiting prenylation of small GTPases. This may explain the reduced incidence of oesophageal adenocarcinoma in statin-users.

publication date

  • February 13, 2021

Research

keywords

  • Atorvastatin
  • Esophageal Neoplasms
  • GTP Phosphohydrolases
  • Leptin
  • Proto-Oncogene Proteins c-akt

Identity

PubMed Central ID

  • PMC8119259

Scopus Document Identifier

  • 85100959029

Digital Object Identifier (DOI)

  • 10.1159/000343896

PubMed ID

  • 33582946

Additional Document Info

volume

  • 476

issue

  • 6