Shenmai injection enhances cisplatin-induced apoptosis through regulation of Mfn2-dependent mitochondrial dynamics in lung adenocarcinoma A549/DDP cells

Abstract

Aim: Chemoresistance is the biggest obstacle in cancer treatment. Our previous study demonstrated that Shenmai injection (SMI), a Chinese herbal medicine, enhanced the antitumor effect of cisplatin via glucose metabolism reprogramming. This study aimed to further determine whether the SMI sensitizes the non-small cell lung cancer (NSCLC) cells to cisplatin through regulation mitochondrial dynamics.

Methods: The Kaplan-Meier Plotter database was used to investigate the relationship between mRNA expression of mitofusin-2 (Mfn2) and the survival analysis of NSCLC patients. The protein expression of Mfn2 in a lung adenocarcinoma tissue chip was detected by immunohistochemistry staining. The expression of Mfn2 and ATAD3A were compared between cisplatin-sensitive A549 and cisplatin-resistant A549/DDP cells. Additionally, A549/DDP cells were co-treated with cisplatin and SMI to detect mitochondrial morphology by fluorescent staining, apoptosis-related protein expression with Western blotting, and mitochondrial membrane potential (ΔΨm) with flow cytometry analysis.

Results: The mean survival time of the Mfn2^low group was significantly lower than that of the Mfn2^high group by Kaplan-Meier Plotter database analysis, and the Mfn2 protein expression level was lower in cancer tissues than in adjacent tissues. The combination of SMI and cisplatin induced dynamic changes in A549/DDP cells, with increased mitochondrial fusion followed by upregulation of Mfn2 and downregulation of ATAD3A and reduced mitochondrial mass and ΔΨm. Moreover, SMI significantly enhanced cisplatin-induced A549/DDP apoptosis, upregulated Bax and the active subunit of caspase-3, and downregulated Bcl-2 expression, as shown via Hoechst staining and flow cytometry analysis.

Conclusion: Our findings suggest SMI enhances cisplatin-induced apoptosis through regulation of Mfn2-dependent mitochondrial dynamics in cisplatin-resistant lung adenocarcinoma cells.

Keywords

SMI / NSCLC / cisplatin-resistant / Mfn2 / mitochondrial dynamics / apoptosis

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