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

• Published in: Cell death & disease 2017-10, Vol.8 (10), p.e3144-e3144
• Main Authors: Fang, Shuhuan, Hong, Honghai, Li, Lei, He, Dan, Xu, Zumin, Zuo, Shaoyuan, Han, Jing, Wu, Qiyuan, Dai, Zhiyu, Cai, Weibin, Ma, Jianxing, Shao, Chunkui, Gao, Guoquan, Yang, Xia
• Format: Article
• Language: English
• Subjects: 13/2; 13/95; 631/80/82/23; 631/80/86; 692/4019/592/16; 692/699/67/1504/1829; Antibodies; Biochemistry; Cell Biology; Cell Culture; Immunology; Life Sciences; Original; original-article
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2017.528

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