Plasminogen kringle 5 suppresses gastric cancer via regulating HIF-1? and GRP78.

ABSTRACT: Inhibition of tumour angiogenesis has an important role in antitumour therapy. However, a recent study indicates that antiangiogenesis therapy may lead to glucose-related protein 78 (GRP78) associated antiapoptotic resistance. The present study aims to elucidate the dual effects of plasminogen kringle 5 (K5) on tumour angiogenesis and apoptosis induction by targeting hypoxia-inducible factor 1? (HIF-1?) and GRP78. Co-immunoprecipitation and western blotting were used for examining the ubiquitination of HIF-1? and analysing angiogenesis and apoptosis-associated proteins. K5 promoted the sumo/ubiquitin-mediated proteasomal degradation of HIF-1? by upregulating von Hippel-Lindau protein under hypoxia, resulting in the reduction of vascular endothelial growth factor and thus suppressing tumour angiogenesis. Furthermore, K5 decreased GRP78 expression via downregulation of phosphorylated extracellular-regulated protein kinase, leading to caspase-7 cleavage and tumour cell apoptosis. Blocking voltage-dependent anion channel abrogated the effects of K5 on both HIF-1? and GRP78. K5 significantly inhibited the growth of gastric carcinoma xenografts by inhibiting both angiogenesis and apoptosis. The dual effects suggest that K5 might be a promising bio-therapeutic agent in the treatment of gastric cancer, particularly in patients who exhibit the induction of GRP78.

SUBMITTER: Fang S 

PROVIDER: S-EPMC5682690 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature