Chidamide and Oxaliplatin Synergistically Inhibit Colorectal Cancer Growth by Regulating the RPS27A-MDM2-P53 Axis

PURPOSE: The present study explored the anti-tumor effects of chidamide plus oxaliplatin on colorectal cancer (CRC) and examined its underlying mechanism. MATERIAL AND METHODS: First, the Combination Index (CI) of chidamide and oxaliplatin was evaluated via CCK-8 assay. Second, the effects of chidam...

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Detalles Bibliográficos
Autores principales: Li, Zhaopeng, Bu, Deyong, Wang, Xiaobin, Zhu, Lin, Lei, Daoyan, Tang, Fengling, Sun, Xianghua, Chen, Cheng, Ji, Xiang, Bai, Song
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2023
Materias:
Original Research
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10475304/
https://www.ncbi.nlm.nih.gov/pubmed/37667747
http://dx.doi.org/10.2147/OTT.S416824
Descripción
Sumario:PURPOSE: The present study explored the anti-tumor effects of chidamide plus oxaliplatin on colorectal cancer (CRC) and examined its underlying mechanism. MATERIAL AND METHODS: First, the Combination Index (CI) of chidamide and oxaliplatin was evaluated via CCK-8 assay. Second, the effects of chidamide and oxaliplatin monotherapy and the combined treatment on cell proliferation, invasion, migration, and apoptosis were detected. Third, whole-transcriptome RNA sequencing (RNA-seq) was performed to seek the potential targeted gene by which chidamide plus oxaliplatin exerted anti-tumor effects. Fourth, the validation of the targeted gene and the signal pathway it regulated were performed. Finally, the anti-tumor effect of chidamide plus oxaliplatin on mice xenograft was examined. RESULTS: Chidamide and oxaliplatin acted synergistically to inhibit CRC growth in vitro and in vivo (CI<1). Besides, compared with oxaliplatin monotherapy, chidamide could significantly enhance oxaliplatin-induced inhibition in cell proliferation, invasion, and migration, and promotion in HCT-116 and RKO cell apoptosis (P<0.05). The RNA-seq displayed that, compared to oxaliplatin monotherapy, RPS27A mRNA was evidently decreased in HCT-116 cells treated with chidamide plus oxaliplatin (P<0.001). Then, we found RPS27A was highly expressed in CRC tissues and CRC cell lines (P<0.001). Silence of RPS27A attenuated proliferation and induced apoptosis in HCT-116 and RKO cells via downregulation of MDM2 expression and upregulation of P53. Next, RPS27A overexpression could partially reverse chidamide plus oxaliplatin induced growth inhibition and apoptosis in HCT-116 and RKO cells (P<0.01). RPS27A overexpression could promote the upregulation of MDM2 and downregulation of P53 after the combined treatment of chidamide with oxaliplatin. CONCLUSION: Chidamide and oxaliplatin acted synergistically to suppress CRC growth by the inhibition of the RPS27A-MDM2-p53 axis.

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