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Adipose tissue secretes the hormone leptin. Leptin is a growth factor for several cell types, including Barrett\u2019s cells and oesophageal adenocarcinoma cells. Statins are associated with reduced rates of Barrett\u2019s 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.<\/jats:p>","DOI":"10.1007\/s11010-021-04067-8","type":"journal-article","created":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T08:43:26Z","timestamp":1613292206000},"page":"2307-2316","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Leptin activates Akt in oesophageal cancer cells via multiple atorvastatin-sensitive small GTPases"],"prefix":"10.1007","volume":"476","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1923-3237","authenticated-orcid":false,"given":"Ian L. 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