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

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 alpha (HIF-1 alpha) and GRP78. Co-immunoprecipitation and western blotting were used for examining the ubiquitination of HIF-1 alpha and analysing angiogenesis and apoptosis-associated proteins. K5 promoted the sumo/ubiquitinmediated proteasomal degradation of HIF-1 alpha 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 alpha 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.