Ropivacaine inhibits the malignant behavior of lung cancer cells by regulating retinoblastoma-binding protein 4

Abstract

Background Ropivacaine is a local anesthetic commonly used in regional nerve blocks to manage perioperative pain during lung cancer surgery. Recently, the antitumor potential of ropivacaine has received considerable attention. Our previous study showed that ropivacaine treatment inhibits the malignant behavior of lung cancer cells in vitro. However, the potential targets of ropivacaine in lung cancer cells have not yet been fully identified. This study aimed to explore the antitumor effects and mechanisms of action of ropivacaine in lung cancer. Methods Lung cancer A549 cells were treated with or without 1 mM ropivacaine for 48 h. Quantitative proteomics was performed to identify the differentially expressed proteins (DEPs) triggered by ropivacaine treatment. STRING and Cytoscape were used to construct protein-protein interaction (PPI) networks and analyze the most significant hub genes. Overexpression plasmids and small interfering RNA were used to modulate the expression of key DEPs in A549 and H1299 cells. MTS, transwell assays, and flow cytometry were performed to determine whether the key DEPs were closely related to the anticancer effect of ropivacaine on the malignant behavior of A549 and H1299 cells. Results Quantitative proteomic analysis identified 327 DEPs (185 upregulated and 142 downregulated proteins) following ropivacaine treatment. Retinoblastoma-binding protein 4 (RBBP4) was one of the downregulated DEPs and was selected as the hub protein. TCGA database showed that RBBP4 was significantly upregulated in lung cancer and was associated with poor patient prognosis. Inhibition of RBBP4 by siRNA resulted in a significant decrease in the proliferation and invasive capacity of lung cancer cells and the induction of cell cycle arrest. Additionally, the results indicated RBBP4 knockdown enhanced antitumor effect of ropivacaine on A549 and H1299 cells. Conversely, the overexpression of RBBP4 using plasmids reversed the inhibitory effects of ropivacaine. Conclusion Our data suggest that ropivacaine suppresses lung cancer cell malignancy by downregulating RBBP4 protein expression, which may help clarify the mechanisms underlying the antitumor effects of ropivacaine.

Interpreting the molecular mechanisms of RBBP4/7 and their roles in human diseases (Review)

“…For example, increased expression of RBBP4 has been linked to mitigating lead-induced neuronal apoptosis, suggesting a potential role in alleviating lead poisoning and related neurological disorders ( 178 ). Additionally, the interaction of RBBP4 with the efficacy of multiple drugs has been extensively studied, including its role in enhancing the sensitivity of GBM cells to TMZ ( 56 , 95 ), suppression of LC cell malignancy via ropivacaine by downregulating RBBP4 ( 179 ), and the identification of the circ-0110498/miR-1287-5p/RBBP4 axis as a novel target for overcoming cisplatin resistance in NSCLC ( 85 ). RBBP4 is also considered a potential target for treating CRC with PPD ( 119 ).…”