Gaudichaudion H inhibits KRAS-mutant pancreatic cancer cell growth through interfering PDEδ-KRAS interaction

Abstract

KRAS mutation results in higher proliferation rates and miserable prognosis of cancers. Targeting the interaction between KRAS and PDE6D provided an alternative strategy to overcome KRAS-mutant pancreatic cancers. Gaudichaudione H (GH) is a prenylated caged xanthone isolated from Garcinia oligantha. In this work, GH was selected as a potential anti-cancer compound by MTT screening of twelve prenylated xanthonoids from G. oligantha. Further studies demonstrated that GH inhibited proliferation of a panel of cancer cell lines and induced pancreatic cancer cell apoptosis. GH suppressed xenograft tumor growth accompanied with decreased phosphorylation of ERK and AKT. Binding with PDEδ and thus interfering the KRAS-PDEδ interaction was verified as the possible mechanism of GH. These findings implicated GH as a promising candidate for the treatment of pancreatic cancers with KRAS mutation, provided novel insight into the underlying mechanisms of GH-induced anticancer effects.