J Cancer 2021; 12(7):1894-1906. doi:10.7150/jca.50306 This issue

Research Paper

JP3 enhances the toxicity of cisplatin on drug-resistant gastric cancer cells while reducing the damage to normal cells

Yi Zhang1,2, Junjie Chen1,2, Zhen Che1,2, Chuanjun Shu3, Dongyin Chen4, Kun Ding1,2, Aiping Li1,2, Jianwei Zhou1,2✉

1. Department of Molecular Cell Biology & Toxicology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
2. The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China.
3. Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China.
4. Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.

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Citation:
Zhang Y, Chen J, Che Z, Shu C, Chen D, Ding K, Li A, Zhou J. JP3 enhances the toxicity of cisplatin on drug-resistant gastric cancer cells while reducing the damage to normal cells. J Cancer 2021; 12(7):1894-1906. doi:10.7150/jca.50306. Available from https://www.jcancer.org/v12p1894.htm

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Abstract

Graphic abstract

Background: Cisplatin (DDP) is a highly effective chemotherapeutic agent to most solid tumors including gastric cancer (GC), however, its clinical value is limited due to severe toxic side effects and secondary drug resistance. JP3, a JWA protein based MMP2-targeted polypeptide, known to inhibit the growth of GC in vivo. However, the bidirectional effects of JP3 in DDP-resistant GC and normal cells have not been demonstrated. The present study aims to investigate the actions of JP3 on protecting normal cells from the toxicity of DDP while enhancing its anti-tumor effects on GC cells.

Methods: Routine laboratory experimental methods including CCK-8 assay, Western blotting, Hoechst staining, immunofluorescence (IF) and qRT-PCR were used in mechanism investigation; protein docking analysis and coimmunoprecipitation (Co-IP) were used for prediction and confirmation of interactions between JP3 and CK2. Mouse xenograft model was used for screening the treatment of JP3 plus DDP on GC growth.

Results: DDP showed similar toxicities to normal cells and DDP-resistant GC cells; JP3 competitively inhibited the binding of XRCC1 to CK2, reduced the DNA repair and anti-apoptosis capacity of DDP-resistant GC cells in combination with DDP treatment; meanwhile, JP3 protected normal cells from DDP-induced oxidative stress and DNA damage through ERK/Nrf2 signaling. JP3 combined with DDP showed similar bidirectional effects in vivo.

Conclusions: JP3 enhanced the inhibitory effects of DDP on tumor growth while reduced toxic side effects of DDP on normal cells. The results of this study provide a new insight for the treatment of drug-resistant GC.

Keywords: Gastric cancer, cisplatin resistance, JP3 polypeptide, synergistic and detoxifying effect.