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

Published on Oct 26, 2017in Cell Death and Disease6.304
· DOI :10.1038/CDDIS.2017.528
Shuhuan Fang6
Estimated H-index: 6
(Guangzhou University of Chinese Medicine),
Shuhuan Fang14
Estimated H-index: 14
(Guangzhou University of Chinese Medicine)
+ 11 AuthorsXia Yang20
Estimated H-index: 20
(SYSU: Sun Yat-sen University)
Sources
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 1α (HIF-1α) and GRP78. Co-immunoprecipitation and western blotting were used for examining the ubiquitination of HIF-1α and analysing angiogenesis and apoptosis-associated proteins. K5 promoted the sumo/ubiquitin-mediated proteasomal degradation of HIF-1α 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-1α 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.
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