Saikosaponin-d mediates FOXG1 to reverse docetaxel resistance in prostate cancer through oxidative phosphorylation

IF 1.5 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2024-07-01 DOI:10.1016/j.mrfmmm.2024.111875

Jun Meng, Bo Yang, Chang Shu, Shuai Jiang

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引用次数: 0

Abstract

Background

Prostate cancer (PCa), a prevalent malignancy worldwide, is frequently identified in advanced stages due to the absence of distinctive early symptoms, thereby culminating in the development of chemotherapy-induced drug resistance. Exploring novel resistance mechanisms and identifying new therapeutic agents can facilitate the advancement of more efficacious strategies for PCa treatment.

Methods

Bioinformatics analysis was employed to investigate the expression of FOXG1 in PCa tissues. Subsequently, qRT-PCR was utilized to validate FOXG1 mRNA expression levels in corresponding PCa cell lines. FOXG1 knockdown was performed, and cell proliferation was assessed using CCK-8 assays, while cell migration and invasion capabilities were evaluated through wound healing and Transwell assays. Western blot and Seahorse analyzer were used to measure oxidative phosphorylation (OXPHOS) levels. Additionally, to explore potential approaches to alleviate PCa drug resistance, this study assessed the impact of biologically active saikosaponin-d (SSd) on PCa malignant progression and resistance by regulating FOXG1 expression.

Results

FOXG1 exhibited high expression in PCa tissues and cell lines. Knockdown of FOXG1 inhibited the proliferation, migration, and invasion of PCa cells, while FOXG1 overexpression had the opposite effect and promoted OXPHOS levels. The addition of an OXPHOS inhibitor prevented this outcome. Finally, SSd was shown to suppress FOXG1 expression and reverse docetaxel resistance in PCa cells through the OXPHOS pathway.

Conclusion

This work demonstrated that SSd mediated FOXG1 to reverse malignant progression and docetaxel resistance in PCa through OXPHOS.

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柴胡皂苷-d 通过氧化磷酸化介导 FOXG1 逆转前列腺癌的多西他赛耐药性

背景：前列腺癌（PCa）是一种全球流行的恶性肿瘤，由于没有明显的早期症状，往往在晚期才被发现，从而导致化疗引起的耐药性的产生。探索新的耐药机制和确定新的治疗药物有助于推进更有效的 PCa 治疗策略：方法：采用生物信息学分析研究 PCa 组织中 FOXG1 的表达。随后，利用 qRT-PCR 验证了 FOXG1 mRNA 在相应 PCa 细胞系中的表达水平。进行 FOXG1 基因敲除，用 CCK-8 检测法评估细胞增殖，用伤口愈合和 Transwell 检测法评估细胞迁移和侵袭能力。利用 Western 印迹和海马分析仪测量氧化磷酸化（OXPHOS）水平。此外，为了探索缓解 PCa 耐药性的潜在方法，本研究还评估了生物活性赛可皂甙-d（SSd）通过调节 FOXG1 表达对 PCa 恶性进展和耐药性的影响：结果：FOXG1在PCa组织和细胞系中高表达。结果：FOXG1 在 PCa 组织和细胞系中高表达，敲除 FOXG1 可抑制 PCa 细胞的增殖、迁移和侵袭，而过表达 FOXG1 则会产生相反的效果，促进 OXPHOS 水平。添加 OXPHOS 抑制剂可防止这种结果。最后，研究表明 SSd 可抑制 FOXG1 的表达，并通过 OXPHOS 途径逆转 PCa 细胞对多西他赛的耐药性：这项研究表明，SSd通过OXPHOS介导FOXG1，逆转了PCa的恶性进展和多西他赛耐药性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis 生物-毒理学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

51 days

期刊介绍： Mutation Research (MR) provides a platform for publishing all aspects of DNA mutations and epimutations, from basic evolutionary aspects to translational applications in genetic and epigenetic diagnostics and therapy. Mutations are defined as all possible alterations in DNA sequence and sequence organization, from point mutations to genome structural variation, chromosomal aberrations and aneuploidy. Epimutations are defined as alterations in the epigenome, i.e., changes in DNA methylation, histone modification and small regulatory RNAs. MR publishes articles in the following areas: Of special interest are basic mechanisms through which DNA damage and mutations impact development and differentiation, stem cell biology and cell fate in general, including various forms of cell death and cellular senescence. The study of genome instability in human molecular epidemiology and in relation to complex phenotypes, such as human disease, is considered a growing area of importance. Mechanisms of (epi)mutation induction, for example, during DNA repair, replication or recombination; novel methods of (epi)mutation detection, with a focus on ultra-high-throughput sequencing. Landscape of somatic mutations and epimutations in cancer and aging. Role of de novo mutations in human disease and aging; mutations in population genomics. Interactions between mutations and epimutations. The role of epimutations in chromatin structure and function. Mitochondrial DNA mutations and their consequences in terms of human disease and aging. Novel ways to generate mutations and epimutations in cell lines and animal models.