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

Shuhuan Fang, Honghai Hong, Lei Li, Dan He, Zumin Xu, Shaoyuan Zuo, Jing Han, Qiyuan Wu, Zhiyu Dai, Weibin Cai, Jianxing Ma, Chunkui Shao, Guoquan Gao, Xia Yang

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)e3144
JournalCell death & disease
Volume8
Issue number10
DOIs
StatePublished - Oct 26 2017

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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    Fang, S., Hong, H., Li, L., He, D., Xu, Z., Zuo, S., Han, J., Wu, Q., Dai, Z., Cai, W., Ma, J., Shao, C., Gao, G., & Yang, X. (2017). Plasminogen kringle 5 suppresses gastric cancer via regulating HIF-1α and GRP78. Cell death & disease, 8(10), e3144. https://doi.org/10.1038/cddis.2017.528