Seker Semih, Sahin Betul, Yerlikaya Azmi
Department of Medical Biology, Faculty of Medicine, Kutahya Health Sciences University, Kutahya, Turkey.
Acibadem Labmed Clinical Laboratories, Istanbul, Turkey.
J Cell Mol Med. 2025 Jan;29(1):e70254. doi: 10.1111/jcmm.70254.
Chemotherapy is a potent tool against cancer, but drug resistance remains a major obstacle. To combat this, understanding the molecular mechanisms behind resistance in cancer cells and the protein expression changes driving these mechanisms is crucial. Targeting the Ubiquitin-Proteasome System (UPS) has proven effective in treating multiple myeloma and shows promise for solid tumours. Despite initial success with the proteasome inhibitor bortezomib, acquired resistance soon after treatment poses a significant challenge to its efficacy. In this study, we explored proteins potentially involved in acquired resistance to bortezomib using label-free nLC-MS/MS proteomic analysis. The investigation revealed 299 proteins with notable differences in expression levels in the bortezomib-resistant PC3 prostate cancer cell line. Using bioinformatics tools, we illustrated the top 10 gene ontology (GO) processes [e.g., translational initiation (p = 5.964E-10), CRD-mediated mRNA stabilisation (p = 1.636E-5), and hydrogen ion transmembrane transport (p = 6.46E-5)] and the top 20 KEGG [e.g., metabolic pathways (p = 7.601E-13), biosynthesis of amino acids (p = 3.834E-12), and chemical carcinogenesis-reactive oxygen species (p = 1.891E-4)] and REACTOME [e.g., metabolism (p = 4.182E-21), translation (p = 9.484E-18), and Nonsense-Mediated Decay (NMD) (p = 1.829E-8)] pathways in the PC3-resistant cells. We further refined our results by comparing them with globally validated TCGA datasets. We correlated the 299 proteins identified through proteomic analysis with tumour aggressiveness and resistance by comparing them with the TCGA nodal metastasis N0 vs. N1 datasets using the UALCAN portal and identified 37 proteins consistent with our results. We believe that a combination of bortezomib with chemotherapeutics targeting these proteins could be effective in overcoming the resistance developed against bortezomib.
化疗是对抗癌症的有力工具，但耐药性仍然是一个主要障碍。为了应对这一问题，了解癌细胞耐药背后的分子机制以及驱动这些机制的蛋白质表达变化至关重要。靶向泛素 - 蛋白酶体系统（UPS）已被证明在治疗多发性骨髓瘤方面有效，并且对实体瘤也有前景。尽管蛋白酶体抑制剂硼替佐米最初取得了成功，但治疗后不久出现的获得性耐药对其疗效构成了重大挑战。在本研究中，我们使用无标记的nLC-MS/MS蛋白质组学分析探索了可能与硼替佐米获得性耐药相关的蛋白质。调查揭示了在硼替佐米耐药的PC3前列腺癌细胞系中表达水平有显著差异的299种蛋白质。使用生物信息学工具，我们阐述了PC3耐药细胞中排名前10的基因本体（GO）过程[例如，翻译起始（p = 5.964E-10）、CRD介导的mRNA稳定（p = 1.636E-5）和氢离子跨膜运输（p = 6.46E-5）]以及排名前20的KEGG[例如，代谢途径（p = 7.601E-13）、氨基酸生物合成（p = 3.834E-12）和化学致癌 - 活性氧（p = 1.891E-4）]和REACTOME[例如，代谢（p = 4.182E-21）、翻译（p = 英文原文中此处有误，请修正后再翻译）和无义介导的衰变（NMD）（p = 1.829E-8）]途径。我们通过将结果与全球验证的TCGA数据集进行比较进一步完善了我们的结果。我们使用UALCAN门户将通过蛋白质组学分析鉴定的299种蛋白质与肿瘤侵袭性和耐药性进行关联，通过将它们与TCGA淋巴结转移N0与N1数据集进行比较，确定了37种与我们结果一致的蛋白质。我们认为，硼替佐米与靶向这些蛋白质的化疗药物联合使用可能有效地克服对硼替佐米产生的耐药性。
