基于生物信息学和体外研究探讨冰片增加曲妥珠单抗耐药型人表皮生长因子受体 2 阳性乳腺癌对曲妥珠单抗敏感性的潜在作用靶点基因的鉴定。
Characterization of Potential Target Genes of Borneol in Increasing Trastuzumab Sensitivity in HER2+ Trastuzumab-Resistant Breast Cancer: Bioinformatics and In Vitro Studies.
机构信息
Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, 55281 Yogyakarta, Indonesia.
Laboratory of Advanced Pharmaceutical Sciences. APSLC Building, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, 55281 Yogyakarta, Indonesia.
出版信息
Asian Pac J Cancer Prev. 2024 May 1;25(5):1623-1634. doi: 10.31557/APJCP.2024.25.5.1623.
OBJECTIVE
The long-term use of trastuzumab (TRZ), a therapeutic agent for human epidermal growth factor receptor 2 (HER2)+ breast cancer subtype (HER2+ BC), induces resistance. Borneol (BOR) exerts anticancer effects on various types of cancer. However, its anticancer effect on HER2+ BC remains unknown. This study aimed to determine the potential target genes of BOR and its effect on overcoming the resistance of HER2+ BC to TRZ.
METHODS
The hub gene of BOR's potential target on HER2+ BC cells was determined via a bioinformatics approach. Resistant HCC1954 cells (HCC1954-TR) were obtained through repeated inducement of HCC1954 cancer cells with TRZ. The cells were then subjected to cytotoxic tests involving single compounds and their combinations. Then, the hub gene expression was determined using quantitative reverse-transcription polymerase chain reaction. The interaction between BOR and selected proteins was measured through molecular docking.
RESULTS
Hub genes IL6, TNF, ESR1, IL1B, CYP19A1, AR, NR3C1, RELA, CYP17A1, and GPT were obtained via a bioinformatics approach. HCC1954-TR cells were successfully established. The TRZ-BOR combination treatment of parental HCC1954 (400 µg/mL and 25 µM) and HCC1954-TR (800 µg/mL and 100 µM) yielded considerably better results compared with BOR or TRZ alone. The expressions of AR, GPT, and ESR1 under the TRZ-BOR combination were notably different compared with those under single exposure. The molecular docking study of CYP19A1, CYP17A1, NR3C1, and IL-1β highlighted the potential interaction between BOR and such proteins.
CONCLUSION
BOR improved the cytotoxic effects of TRZ on HCC1954 and HCC1954-TR cell lines, where it specifically targets AR, ESR1, and GPT genes. In addition, the BOR effect, which counteracted the resistance of HCC1954-TR cells to TRZ, was mediated by genes CYP19A1, CYP17A1, NR3C1, IL-1, and RELA. However, additional research is required to validate their role in BOR activity to circumvent the resistance of HER2+ BC to TRZ.
目的
曲妥珠单抗（TRZ）是一种用于治疗人表皮生长因子受体 2（HER2）+乳腺癌亚型（HER2+BC）的治疗药物，长期使用会产生耐药性。龙脑（BOR）对多种类型的癌症具有抗癌作用。然而，其对 HER2+BC 的抗癌作用尚不清楚。本研究旨在确定 BOR 的潜在靶基因及其克服 HER2+BC 对 TRZ 耐药的作用。
方法
通过生物信息学方法确定 BOR 对 HER2+BC 细胞的潜在靶基因。通过反复诱导 HCC1954 癌细胞使用 TRZ 获得耐药 HCC1954 细胞（HCC1954-TR）。然后对细胞进行涉及单化合物及其组合的细胞毒性试验。然后使用定量逆转录聚合酶链反应测定靶基因的表达。通过分子对接测量 BOR 与选定蛋白之间的相互作用。
结果
通过生物信息学方法获得了 IL6、TNF、ESR1、IL1B、CYP19A1、AR、NR3C1、RELA、CYP17A1 和 GPT 等关键基因。成功建立了 HCC1954-TR 细胞。与单独使用 BOR 或 TRZ 相比，亲本 HCC1954（400μg/mL 和 25μM）和 HCC1954-TR（800μg/mL 和 100μM）的 TRZ-BOR 联合治疗产生了更好的效果。与单独暴露相比，TRZ-BOR 联合治疗下 AR、GPT 和 ESR1 的表达明显不同。CYP19A1、CYP17A1、NR3C1 和 IL-1β 的分子对接研究突出了 BOR 与这些蛋白之间的潜在相互作用。
结论
BOR 提高了 TRZ 对 HCC1954 和 HCC1954-TR 细胞系的细胞毒性作用，其特异性靶向 AR、ESR1 和 GPT 基因。此外，BOR 作用通过 CYP19A1、CYP17A1、NR3C1、IL-1 和 RELA 基因介导，拮抗 HCC1954-TR 细胞对 TRZ 的耐药性。然而，需要进一步的研究来验证它们在 BOR 活性中的作用，以规避 HER2+BC 对 TRZ 的耐药性。
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