Alhamed Abdullah S, El-Wetidy Mohammad S, Abdelwahed Mervat M, Attia Sabry M, Alabkka Abdulrahman M, Alaraj Saleh A, Alhazzani Khalid, Alanazi Ahmed Z, Almutairi Faris, Alotibi Ibrahem A, Alqinyah Mohammed
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
College of Medicine Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia.
Int J Med Sci. 2025 Mar 31;22(9):2031-2039. doi: 10.7150/ijms.111217. eCollection 2025.
Chemotherapeutic drugs, like cisplatin, function by damaging genomic DNA, thus inducing cell apoptosis. Cancer cells can enhance their DNA repair capacity, leading to chemotherapeutic resistance. Nucleotide excision repair (NER) involves repairing DNA adducts and crosslinks caused by chemotherapeutic agents. Transforming growth factor-beta (TGF-β) pathway contributes to carcinogenesis, DNA repair alteration, and chemoresistance. However, the connection between TGF-β pathway, NER function alteration, and resistance to cisplatin therapy remains elusive. Therefore, the objective of current study was to fill this gap by assessing the impact of TGF-β inhibition and activation on cisplatin-induced antiproliferation, apoptosis, and DNA damage using the MTT assay, flow cytometry analysis, and COMET assay, respectively. Four NER genes, XPA, XPB, XPC, and XPF, were measured using Real-time Polymerase Chain Reaction (qPCR). MDA-MB-231 cell line was utilized as a model of breast cancer. Blockade of the TGF-β pathway strengthened cisplatin cytotoxicity, whereas induction of the TGF-β pathway suppressed cisplatin cytotoxicity. In cisplatin-treated breast cancer cells, DNA damage significantly increased upon the TGF-β pathway inhibition. Conversely, cisplatin-induced DNA damage decreased significantly upon TGF-β pathway stimulation. Finally, cisplatin caused an overexpression of the four NER genes which was curtailed and augmented by TGF-β inhibition and stimulation, respectively. Overall, this study presented evidence of the impact exerted by TGF-β pathway on NER and cisplatin sensitivity of breast cancer cells.
化疗药物，如顺铂，通过损伤基因组DNA发挥作用，从而诱导细胞凋亡。癌细胞可增强其DNA修复能力，导致化疗耐药。核苷酸切除修复（NER）涉及修复由化疗药物引起的DNA加合物和交联。转化生长因子-β（TGF-β）信号通路参与致癌作用、DNA修复改变和化疗耐药。然而，TGF-β信号通路、NER功能改变与顺铂治疗耐药之间的联系仍不清楚。因此，本研究的目的是通过分别使用MTT法、流式细胞术分析和彗星试验评估TGF-β抑制和激活对顺铂诱导的细胞增殖抑制、凋亡和DNA损伤的影响，来填补这一空白。使用实时聚合酶链反应（qPCR）检测四个NER基因XPA、XPB、XPC和XPF。MDA-MB-231细胞系用作乳腺癌模型。阻断TGF-β信号通路增强了顺铂的细胞毒性，而诱导TGF-β信号通路则抑制了顺铂的细胞毒性。在顺铂处理的乳腺癌细胞中，TGF-β信号通路抑制后DNA损伤显著增加。相反，TGF-β信号通路刺激后顺铂诱导的DNA损伤显著减少。最后，顺铂导致四个NER基因的过表达，而TGF-β抑制和刺激分别使其减少和增加。总体而言，本研究提供了证据，证明TGF-β信号通路对乳腺癌细胞的NER和顺铂敏感性有影响。
