GW4869 Can Inhibit Epithelial-Mesenchymal Transition and Extracellular HSP90α in Gefitinib-Sensitive NSCLC Cells

Abstract

Objective

GW4869 is an exosomal inhibitor. It is necessary to delay the occurrence of gefitinib resistance during non-small-cell lung cancer (NSCLC) treatment. This study aimed to investigate the anti-tumor effects of GW4869 on epithelial-mesenchymal transition (EMT) and expression of extracellular heat shock protein 90α (eHSP90α) that contributes to acquired resisitance. Our study provides a new sight into the treatment of EGFR-mutated NSCLC.

Materials and Methods

We performed western blotting to detect levels of EMT and eHSP90α. Wound healing and transwell assays were performed to evaluate the behavioral dynamics of EMT. A nude mouse model of HCC827 was established in vivo.

Results

GW4869 inhibited the expression of eHSP90α, EMT, invasion and migration abilities of HCC827 and PC9. GW4869 enhanced sensitivity to gefitinib in BALB/c nude mice bearing tumors of HCC827.

Conclusion

These studies suggest that GW4869 can inhibit EMT and extracellular HSP90α, providing new strategies for enhancing gefitinib sensitivity in NSCLC.

Keywords:

• GW4869
• EMT
• gefitinib-sensitive NSCLC
• eHSP90α

Abbreviations

HSP90α, heat shock protein alpha; EMT, epithelial-mesenchymal transition; NSCLC, non-small-cell lung cancer; EGFR, epidermal growth factor receptor; EGFR-TKI, EGFR-tyrosine kinase inhibitor; MVBs, multivesicular bodies; RASP, resistance-associated secretory phenotype; EV, extracellular vesicles; hrHSP90α, human recombinant HSP90α; RIPA, radioimmunoprecipitation assay; PVDF, polyvinylidene difluoride.

Ethical Statement

All animal experiments in this study complied with the Animal Research Reporting of In Vivo Experiments (ARRIVE) guidelines 4, as well as were approved by the Ethics Committee of Nanfang Hospital (Guangdong, China) (Medical Ethics No. NFEC-2019-065).

Acknowledgments

This study was supported by the National Natural Science Foundation of China (81470228 and 81670026) and Natural Science Foundation of Guangdong Province (2017A030313849).Sincerely thanks to the generous donation of PC9 from the Guangdong Lung Cancer Institute.

Disclosure

The authors report no conflicts of interest in this work.