Generic placeholder image

Current Cancer Drug Targets

Author(s): Yan Li*, Qi-Jing Guo, Rong Chen, LingLin Zhao, Xianshu Cui, Yingfang Deng and Yu-Shuang Luo*

DOI: 10.2174/1568009624666230915111239

DownloadDownload PDF Flyer Cite As
Crocin Combined with Cisplatin Regulates Proliferation, Apoptosis, and EMT of Gastric Cancer Cells via the FGFR3/MAPK/ERK Pathway In vitro and In vivo

Page: [835 - 845] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Introduction: Cisplatin (DDP)-based chemotherapy remains the main therapeutic strategy for human gastric cancer (GC). Combination therapy with Chinese medicine monomers and DDP has been investigated as a means to enhance the anti-tumor effect of DDP while reducing toxicity.

Material and Methods: Previous studies have shown that crocin combined with DDP can inhibit the apoptosis of BG-823 GC cells. However, the mechanism of this combination therapy in inhibiting GC is not fully unclear. In this study, we measured the IC50 values of crocin combined with DDP in AGS cells and assessed its effect on cell proliferation using an MTT assay. Furthermore, we assessed apoptosis, cell migration, and EMT-related protein levels by using flow cytometry, scratch assay, and Western blotting, respectively. Our results showed that crocin combined with DDP inhibited the proliferation, induced apoptosis, and inhibited invasion and EMT. Next, we performed RNA sequence and KEGG enrichment analysis on GC cells treated with Crocin+DDP.

Results: The results showed that the most significant factor down-regulated by this combination therapy was Fibroblast growth factor receptor 3 (FGFR3) expression and that a differential gene was enriched in the MAPK/ERK pathway. We further constructed an FGFR3 OE transfection plasmid to overexpress FGFR3 and evaluate its effects on proliferation, apoptosis, migration, EMT, and MAPK/ERK pathway proteins in GC cells. We also conducted subcutaneous tumorigenesis experiments in nude mice to evaluate the effects of crocin and DDP on the progression of GC xenografts in vivo. Finally, we performed a rescue experiment using the MAPK/ERK pathway inhibitor PD184352.

Conclusion: Our results showed that up-regulation of FGFR3 reversed the inhibitory effect of crocin+DDP on the MAPK/ERK signaling pathway. Still, this effect could be counteracted by PD184352, which simultaneously regulated the proliferation, apoptosis, and EMT of AGS cells. In conclusion, crocin, combined with DDP, inhibits proliferation, apoptosis, and EMT of GC through the FRFR3/MAPK/ERK pathway.

Graphical Abstract

[1]
Wagner, A.D.; Syn, N.L.; Moehler, M; Grothe, W; Yong, W.P.; Tai, B.C.; Ho, J; Unverzagt, S. Chemotherapy for advanced gastric cancer. Cochrane Database Sys. Rev., 2017, 8(8), CD004064.
[2]
Sun, M.Y.; Sun, J.; Tao, J.; Yuan, Y.X.; Ni, Z.H.; Tang, Q.F. Zuo Jin wan reverses DDP resistance in gastric cancer through ROCK/PTEN/PI3K signaling pathway. Evid. Based Complement. Alternat. Med., 2018, 2018(2), 1-11.
[http://dx.doi.org/10.1155/2018/4278568] [PMID: 30622602]
[3]
Manohar, S.; Leung, N. Cisplatin nephrotoxicity: A review of the literature. J. Nephrol., 2018, 31(1), 15-25.
[http://dx.doi.org/10.1007/s40620-017-0392-z] [PMID: 28382507]
[4]
Rybak, L.; Mukherjea, D.; Ramkumar, V. Mechanisms of cisplatin-induced ototoxicity and prevention. Semin. Hear., 2019, 40(2), 197-204.
[http://dx.doi.org/10.1055/s-0039-1684048] [PMID: 31036996]
[5]
Lou, J.S.; Zhao, L.P.; Huang, Z.H.; Chen, X.Y.; Xu, J.T.; Tai, W.C.S.; Tsim, K.W.K.; Chen, Y.T.; Xie, T. Ginkgetin derived from Ginkgo biloba leaves enhances the therapeutic effect of cisplatin Via ferroptosis-mediated disruption of the Nrf2/HO-1 axis in EGFR wild-type non-small-cell lung cancer. Phytomedicine, 2021, 80, 153370.
[http://dx.doi.org/10.1016/j.phymed.2020.153370] [PMID: 33113504]
[6]
Liu, L; Fan, J; Ai, G; Liu, J; Luo, N; Li, C; Cheng, Z Berberine in combination with cisplatin induces necroptosis and apoptosis in ovarian cancer cells. Biol Res., 2019, 52(1), 37.
[http://dx.doi.org/10.1186/s40659-019-0243-6]
[7]
Chen, S.S.; Gu, Y.; Lu, F.; Qian, D.P.; Dong, T.T.; Ding, Z.H.; Zhao, S.; Yu, Z.H. Antiangiogenic effect of crocin on breast cancer cell MDA-MB-231. J. Thorac. Dis., 2019, 11(11), 4464-4473.
[http://dx.doi.org/10.21037/jtd.2019.11.18] [PMID: 31903234]
[8]
Luo, Y.; Yu, P.; Zhao, J.; Guo, Q.; Fan, B.; Diao, Y.; Jin, Y.; Wu, J.; Zhang, C. Inhibitory effect of crocin against gastric carcinoma via regulating TPM4 gene. OncoTargets Ther., 2021, 14(14), 111-122.
[http://dx.doi.org/10.2147/OTT.S254167] [PMID: 33442270]
[9]
Zhang, Y.; Zhu, M.; Krishna Mohan, S.; Hao, Z. Crocin treatment promotes the oxidative stress and apoptosis in human thyroid cancer cells FTC-133 through the inhibition of STAT/JAK signaling pathway. J. Biochem. Mol. Toxicol., 2021, 35(1), e22608.
[http://dx.doi.org/10.1002/jbt.22608] [PMID: 32886819]
[10]
Wang, G.; Zhang, B.; Wang, Y.; Han, S.; Wang, C. Crocin promotes apoptosis of human skin cancer cells by inhibiting the JAK/STAT pathway. Exp. Ther. Med., 2018, 16(6), 5079-5084.
[http://dx.doi.org/10.3892/etm.2018.6865] [PMID: 30542463]
[11]
Luo, Y.; Cui, S.; Tang, F.; Shen, C.; Qi, Y.; Lu, D.; Ma, L.; Yang, Y.; Li, Y.; Chen, R.; Ri-Li, G.E. The combination of crocin with cisplatin suppresses growth of gastric carcinoma cell line BGC-823 and promotes cell apoptosis. Pak. J. Pharm. Sci., 2017, 30(5), 1629-1634.
[PMID: 29084683]
[12]
Hart, K.C.; Robertson, S.C.; Donoghue, D.J. Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis, Stat activation, and phosphatidylinositol 3-kinase activation. Mol. Biol. Cell, 2001, 12(4), 931-942.
[http://dx.doi.org/10.1091/mbc.12.4.931] [PMID: 11294897]
[13]
Jing, W; Wang, G; Cui, Z; Xiong, G; Jiang, X; Li, Y; Li, W; Han, B; Chen, S; Shi, B. FGFR3 destabilizes PD-L1 via NEDD4 to control T-cell-mediated bladder cancer immune surveillance. Cancer Res., 2022, 82(1), 114-129.
[14]
Long, X; Shi, Y; Ye, P; Guo, J; Zhou, Q; Tang, Y. MicroRNA-99a suppresses breast cancer progression by targeting FGFR3. Front. Oncol., 2020, 9, 1473.
[http://dx.doi.org/10.3389/fonc.2019.01473]
[15]
Babina, I.S.; Turner, N.C. Advances and challenges in targeting FGFR signalling in cancer. Nat. Rev. Cancer, 2017, 17(5), 318-332.
[http://dx.doi.org/10.1038/nrc.2017.8] [PMID: 28303906]
[16]
Hu, K.; Yu, W.; Ajayi, O.; Li, L.; Huang, Z.; Rong, Q.; Wang, S.; Wu, Q.F. Integrated analysis of whole genome and transcriptome sequencing in a young patient with gastric cancer provides insights for precision therapy. Oncol. Lett., 2020, 20(4), 1.
[http://dx.doi.org/10.3892/ol.2020.11976] [PMID: 32863928]
[17]
Piro, G; Carbone, C; Cataldo, I; Di Nicolantonio, F; Giacopuzzi, S; Aprile, G; Simionato, F; Boschi, F; Zanotto, M; Mina, MM; Santoro, R; Merz, V; Sbarbati, A; de Manzoni, G; Scarpa, A; Tortora, G; Melisi, D An FGFR3 autocrine loop sustains acquired resistance to trastuzumab in gastric cancer patients. Clin Cancer Res., 2016, 22(24), 6164-6175.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0178]
[18]
Yeung, K.T.; Yang, J. Epithelial-mesenchymal transition in tumor metastasis. Mol. Oncol., 2017, 11(1), 28-39.
[http://dx.doi.org/10.1002/1878-0261.12017] [PMID: 28085222]
[19]
Ribatti, D.; Tamma, R.; Annese, T. Epithelial-mesenchymal transition in cancer: A historical overview. Transl. Oncol., 2020, 13(6), 100773.
[http://dx.doi.org/10.1016/j.tranon.2020.100773] [PMID: 32334405]
[20]
Pastushenko, I.; Blanpain, C. EMT transition states during tumor progression and metastasis. Trends Cell Biol., 2019, 29(3), 212-226.
[http://dx.doi.org/10.1016/j.tcb.2018.12.001] [PMID: 30594349]
[21]
Zhang, R; Zhao, H; Yuan, H; Wu, J; Liu, H; Sun, S; Zhang, Z; Wang, J. CircARVCF contributes to cisplatin resistance in gastric cancer by altering miR-1205 and FGFR1. Front. Genet., 2021, 25(12), 767590.
[http://dx.doi.org/10.3389/fgene.2021.767590]
[22]
Gao, X.; Liu, H.; Wu, Q.; Wang, R.; Huang, M.; Ma, Q.; Liu, Y. miRNA-381-3p functions as a tumor suppressor to inhibit gastric cancer by targeting fibroblast growth factor receptor-2. Cancer Biother. Radiopharm., 2022, 28(6), 396-404.
[PMID: 35029520]
[23]
Zhang, X.; Zhang, X.; Han, R.; Wang, Z.; Yang, Q.; Huang, Y.; Yan, Y. BLU-554, A selective inhibitor of FGFR4, exhibits anti-tumour activity against gastric cancer in vitro. Biochem. Biophys. Res. Commun., 2022, 595(595), 22-27.
[http://dx.doi.org/10.1016/j.bbrc.2022.01.067] [PMID: 35093636]
[24]
Sun, Y.; Li, G.; Zhu, W.; He, Q.; Liu, Y.; Chen, X.; Liu, J.; Lin, J.; Han-Zhang, H.; Yang, Z.; Lizaso, A.; Xiang, J.; Mao, X.; Liu, H.; Gao, Y. A comprehensive pan-cancer study of fibroblast growth factor receptor aberrations in Chinese cancer patients. Ann. Transl. Med., 2020, 8(20), 1290.
[http://dx.doi.org/10.21037/atm-20-5118] [PMID: 33209870]
[25]
Aviles, R.J.; Annex, B.H.; Lederman, R.J. Testing clinical therapeutic angiogenesis using basic fibroblast growth factor (FGF-2). Br. J. Pharmacol., 2003, 140(4), 637-646.
[http://dx.doi.org/10.1038/sj.bjp.0705493] [PMID: 14534147]
[26]
Reichert, J.M.; Rosensweig, C.J.; Faden, L.B.; Dewitz, M.C. Monoclonal antibody successes in the clinic. Nat. Biotechnol., 2005, 23(9), 1073-1078.
[http://dx.doi.org/10.1038/nbt0905-1073] [PMID: 16151394]
[27]
Krause, D.S.; Van Etten, R.A. Tyrosine kinases as targets for cancer therapy. N. Engl. J. Med., 2005, 353(2), 172-187.
[28]
Garber, K. The second wave in kinase cancer drugs. Nat. Biotechnol., 2006, 24(2), 127-130.
[http://dx.doi.org/10.1038/nbt0206-127] [PMID: 16465146]
[29]
di Martino, E; Alder, O; Hurst, C.D. ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer. Sci. Rep., 2019, 9(1), 5740.
[30]
Ban, M.J.; Byeon, H.K.; Yang, Y.J.; An, S.; Kim, J.W.; Kim, J.H.; Kim, D.H.; Yang, J.; Kee, H.; Koh, Y.W. Fibroblast growth factor receptor 3-mediated reactivation of ERK signaling promotes head and neck squamous cancer cell insensitivity to MEK inhibition. Cancer Sci., 2018, 109(12), 3816-3825.
[http://dx.doi.org/10.1111/cas.13839] [PMID: 30343534]
[31]
Nelson, K.N.; Meyer, A.N.; Wang, C.G.; Donoghue, D.J. Oncogenic driver FGFR3-TACC3 is dependent on membrane trafficking and ERK signaling. Oncotarget, 2018, 9(76), 34306-34319.
[http://dx.doi.org/10.18632/oncotarget.26142]