Department of Thoracic Surgery, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China.
Department of Medical Record, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China.
Pharmacology. 2024;109(4):202-215. doi: 10.1159/000536557. Epub 2024 Apr 22.
INTRODUCTION: Studies have shown that glycolysis metabolism affects the resistance or sensitivity of tumors to chemotherapy drugs. Emerging from recent research, a paradigm-shifting revelation has unfolded, elucidating the oncogenic nature of SKA3 within the context of lung adenocarcinoma (LUAD). Consequently, this work was designed to delve into the effects of SKA3 on glycolysis and cisplatin (CDDP) resistance in LUAD cells and to find new possibilities for individualized treatment of LUAD. METHODS: LUAD mRNA expression data from the TCGA database were procured to scrutinize the differential expression patterns of SKA3 in both tumor and normal tissues. GSEA and Pearson correlation analyses were employed to elucidate the impact of SKA3 on signaling pathways within the context of LUAD. In order to discern the upstream regulatory mechanisms, the ChEA and JASPAR databases were utilized to predict the transcription factors and binding sites associated with SKA3. qRT-PCR and Western blot were implemented to assay the mRNA and protein expression levels of SKA3 and TFAP2A. Chromatin immunoprecipitation and dual-luciferase assays were performed to solidify the binding relationship between the two. Extracellular acidification rate, glucose consumption, lactate production, and glycolysis-related proteins (HK2, GLUT1, and LDHA) were used to evaluate the level of glycolysis. Cell viability under CDDP treatment was determined utilizing the CCK-8, allowing for the calculation of IC50. The expression levels of SKA3 and TFAP2A proteins were detected by immunohistochemistry (IHC). RESULTS: SKA3 exhibited upregulation in LUAD tissues and cell lines, establishing a direct linkage with glycolysis pathway. Overexpression of SKA3 fostered glycolysis in LUAD, resulting in reduced sensitivity toward CDDP treatment. The upstream transcription factor of SKA3, TFAP2A, was also upregulated in LUAD and could promote SKA3 transcription. Overexpression of TFAP2A also fostered the glycolysis of LUAD. Rescue assays showed that TFAP2A promoted glycolysis in LUAD cells by activating SKA3, reducing the sensitivity of LUAD cells to CDDP. The IHC analysis revealed a positive correlation between high expression of SKA3 and TFAP2A and CDDP resistance. CONCLUSION: In summary, TFAP2A can transcriptionally activate SKA3, promote glycolysis in LUAD, and protect LUAD cells from CDDP treatment, indicating that targeting the TFAP2A/SKA3 axis may become a plausible and pragmatic therapeutic strategy for the clinical governance of LUAD.
简介：研究表明，糖酵解代谢会影响肿瘤对化疗药物的耐药性或敏感性。最近的研究揭示了一个具有颠覆性的新发现，即在肺腺癌（LUAD）中，SKA3 具有致癌性。因此，本研究旨在探讨 SKA3 对 LUAD 细胞糖酵解和顺铂（CDDP）耐药性的影响，并为 LUAD 的个体化治疗寻找新的可能性。 方法：从 TCGA 数据库中获取 LUAD mRNA 表达数据，以研究 SKA3 在肿瘤和正常组织中的差异表达模式。采用 GSEA 和 Pearson 相关性分析探讨 SKA3 对 LUAD 中信号通路的影响。为了识别上游调控机制，使用 ChEA 和 JASPAR 数据库预测与 SKA3 相关的转录因子和结合位点。采用 qRT-PCR 和 Western blot 检测 SKA3 和 TFAP2A 的 mRNA 和蛋白表达水平。采用染色质免疫沉淀和双荧光素酶报告基因检测实验验证两者之间的结合关系。通过检测细胞外酸化率、葡萄糖消耗、乳酸生成和糖酵解相关蛋白（HK2、GLUT1 和 LDHA）来评估糖酵解水平。通过 CCK-8 测定法检测 CDDP 处理下细胞的存活率，从而计算 IC50。采用免疫组织化学（IHC）检测 SKA3 和 TFAP2A 蛋白的表达水平。 结果：SKA3 在 LUAD 组织和细胞系中表达上调，与糖酵解途径直接相关。SKA3 的过表达促进了 LUAD 的糖酵解，导致对 CDDP 治疗的敏感性降低。SKA3 的上游转录因子 TFAP2A 在 LUAD 中也上调，并能促进 SKA3 的转录。TFAP2A 的过表达也促进了 LUAD 的糖酵解。挽救实验表明，TFAP2A 通过激活 SKA3 促进 LUAD 细胞的糖酵解，降低 LUAD 细胞对 CDDP 的敏感性。IHC 分析显示，SKA3 和 TFAP2A 的高表达与 CDDP 耐药性呈正相关。 结论：综上所述，TFAP2A 可以转录激活 SKA3，促进 LUAD 的糖酵解，并保护 LUAD 细胞免受 CDDP 治疗，表明靶向 TFAP2A/SKA3 轴可能成为 LUAD 临床治疗的一种合理且实用的治疗策略。
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