Salvianolic acid A inhibits tumor-associated angiogenesis by blocking GRP78 secretion

Abstract

Glucose-regulated protein 78 (GRP78) often highly expresses in a wide range of tumors, which plays promotive functions due to its diversity of location in the development of tumor. Particularly, GRP78 can be secreted into microenvironment by tumor cells through the pathway of exosome, which promotes proliferation, angiogenesis, and drug resistance in cancer cells. Hence, we discovered a potential inhibitor to block GRP78 secretion. We screened five small molecules that may interact with the GRP78 from 51 traditional Chinese medicine molecules by molecular docking. By using western blot, we found that one of the molecules can inhibit the secretion of GRP78, which is salvianolic acid A (SAA). Further, SAA could interact with the lysine residue 633 (K633) of GRP78, which inhibited GRP78 secretion. Moreover, SAA-GRP78 interaction can facilitate GRP78 of cytosol sorted into lysosome for degradation rather than exosome. In conclusion, our research revealed that SAA has the novel function of anti-angiogenesis via the tumor environment.

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Abbreviations

SAA:

Salvianolic acid A

GRP78:

Glucose-regulated protein 78

TME:

Tumor microenvironment

K633:

Lysine residue 633

PD:

Platycodin D

SBD:

Substrate-binding domain

Ub:

Ubiquitination

EGFR:

Epidermal growth factor receptor

VEGF:

Vascular endothelial growth factor

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Funding

This work was financially supported by the National Natural Science Foundation of China [No. 31770382], National Natural Science Foundation of China [No. 81803791], Shanxi Province Science Foundation for Youths [201601D021108], and “1331 Project” Collaborative Innovation Center [1331 CIC].

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Contributions

ZL and LZ conceived and designed research. YY conducted experiments. HL and SG contributed new reagents or analytical tools. XL analyzed data. YY wrote the manuscript. All authors read and approved the manuscript.

Corresponding author

Correspondence to Zhuoyu Li.

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All of the mouse experiments were approved by the Institutional Animal Care and Use Committee of Shanxi University (Taiyuan, China). All of the experimental procedures were performed in accordance with the protocols and ethical regulations approved by the Institutional Animal Care and Use Committee of Shanxi University (Taiyuan, China).

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The authors declare that they have no conflicts of interest.

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Yang, Y., Zhang, L., La, X. et al. Salvianolic acid A inhibits tumor-associated angiogenesis by blocking GRP78 secretion. Naunyn-Schmiedeberg's Arch Pharmacol 392, 467–480 (2019). https://doi.org/10.1007/s00210-018-1585-2

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Keywords

  • Tumor-secreted GRP78
  • Salvianolic acid A
  • Exosome
  • Interaction
  • Angiogenesis