CAMK2a Regulates Paclitaxel Resistance in Oral Squamous Cell Carcinoma Cells by Activating the ERK Signaling Pathway

Wang Junfeng, Chen Hongli, Chen Jiao, Feng Yun, Yuan Yao, Zhang Ping

Abstract

Objective

To investigate the molecular mechanisms by which calcium signaling pathways regulate the paclitaxel resistance and the survival of oral squamous cell carcinoma (OSCC) cells.

Methods 

A paclitaxel-resistant OSCC cell model was established through continuous low-dose paclitaxel induction with dose escalation. The stability of the paclitaxel-resistant model was assessed using the Cell Counting Kit-8 (CCK-8) and imaging flow cytometry. RNA sequencing (RNA-seq) was performed to analyze differentially expressed genes and functional enrichment. Quantitative real-time PCR (qPCR) was conducted to analyze the differential expression of the CAMK2a gene. Protein expression levels were assessed by Western blot (WB). CAMK2a expression was inhibited using KN93 and CAMK2a small interfering RNA (siRNA).

Results 

A paclitaxel-resistant OSCC cell model was successfully established. Gene Ontology (GO) enrichment analysis of the sequencing data revealed differences in the calcium signaling pathways in resistant cells. The expression of multiple genes of the CAMK2 family was upregulated, and CAMK2a expression increased by 12% (P < 0.05). After inhibiting CAMK2a by treatment with KN93, an inhibitor, and CAMK2a siRNA-mediated gene knockdown, the proliferative capacity of paclitaxel-resistant cells decreased by 35% (P < 0.0001). Furthermore, the expression levels of phosphorylated Erk1/2 (p-Erk1/2) and its downstream signaling molecules also decreased following CAMK2a inhibition.

Conclusion

CAMK2a regulates drug resistance and the proliferative capacity of paclitaxel-resistant cells by activating the MAPK-Erk1/2 pathway and represents a potential new therapeutic target for clinical treatment of drug-resistant patients.

 

Keywords: Oral squamous cell carcinoma, Calcium signaling pathway, Paclitaxel resistance, CAMK2a, Target


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References


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