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

Abstract

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.

Keywords:

• chidamide
• oxaliplatin
• colorectal cancer
• synergism

Ethics Approval and Informed Consent

The procedures related to human tissues from CRC patients in this research was approved by the Medical Ethics Committee of The First Affiliated Hospital of Kunming Medical University (approval No. 2022. L. 56). All procedures involving human individuals in our study were performed in line with the Declaration of Helsinki. All procedures on mice were operated in accordance with the National Institutes of Health (NIH) regulations related to the use and care of experimental animals, which were granted by the Animal Care Ethics Committee of Kunming Medical University (No. KMMU20220887).

Consent for Publication

All authors of the present study have carefully read the final manuscript and agreed to publish it in your journal.

Acknowledgments

Zhaopeng Li and Deyong Bu are co-first authors for this study. We are extremely thankful to the teachers of Department of Gastrointestinal Surgery who provided histological samples from CRC patients for us. We also highly acknowledge the Transcriptomic Platform providing by Kunming Institute of zoology, Chinese academy of sciences for cDNA libraries sequencing.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This study was supported by the Clinical Research Center for Geriatric Diseases of Yunnan Province - diagnosis and treatment of geriatric comorbidity and clinical translational research. (No. 202102AA310069).