Title:Crocin Combined with Cisplatin Regulates Proliferation, Apoptosis, and
EMT of Gastric Cancer Cells via the FGFR3/MAPK/ERK Pathway In
vitro and In vivo
Volume: 24
Issue: 8
Author(s): Yan Li*, Qi-Jing Guo, Rong Chen, LingLin Zhao, Xianshu Cui, Yingfang Deng and Yu-Shuang Luo*
Affiliation:
- Department of Oncology, Affiliated Hospital of Qinghai University, XiNing, Qinghai, China
- Department of Oncology, Affiliated Hospital of Qinghai University, XiNing, Qinghai, China
- High Altitude Medicine
Research Center, Key Laboratory of High Altitude Medicine, Ministry of Education Qinghai-Utah Joint Research Key
Lab for High Altitude Medicine Qinghai University, XiNing, Qinghai, 810001, China
Keywords:
Crocin, cisplatin, fibroblast growth factor receptor 3, gastric cancer, MAPK/ERK, signaling pathway.
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.
