Bioinformatics and In Vitro Study Reveal ERα as The Potential Target Gene of Honokiol to Enhance Trastuzumab Sensitivity in HER2+ Trastuzumab-Resistant Breast Cancer Cells

• Published in: Computational biology and chemistry 2024-08, Vol.111, p.108084, Article 108084
• Main Authors: Putra, I Made Rhamanadana, Lestari, Intan Ayu, Fatimah, Nurul, Hanif, Naufa, Ujiantari, Navista Sri Octa, Putri, Dyaningtyas Dewi Pamungkas, Hermawan, Adam
• Format: Article
• Language: English
• Subjects: Allyl Compounds; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biphenyl Compounds - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Computational Biology; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - drug effects; Drug Screening Assays, Antitumor; Estrogen receptor; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Female; HER2; Honokiol; Humans; Lignans - chemistry; Lignans - pharmacology; Molecular Docking Simulation; Phenols; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Trastuzumab; Trastuzumab - chemistry; Trastuzumab - pharmacology; Trastuzumab resistance
• ISSN: 1476-9271; 1476-928X; 1476-928X
• DOI: 10.1016/j.compbiolchem.2024.108084

Trastuzumab resistance presents a significant challenge in the treatment of HER2+ breast cancer, necessitating the investigation of combination therapies to overcome this resistance. Honokiol, a compound with broad anticancer activity, has shown promise in this regard. This study aims to discover the effect of honokiol in increasing trastuzumab sensitivity in HER2+ trastuzumab-resistant breast cancer cells HCC1954 and the underline mechanisms behind. A bioinformatics study performed to explore the most potential target hub gene for honokiol in HER2+ breast cancer. Honokiol, trastuzumab and combined treatment cytotoxicity activity was then evaluated in both parental HCC1954 and trastuzumab resistance (TR-HCC1954) cells using MTT assay. The expression levels of these hub genes were then analyzed using qRT-PCR and those that could not be analyzed were subjected to molecular docking to determine their potential. Honokiol showed a potent cytotoxicity activity with an IC50 of 41.05 μM and 69.61 μM in parental HCC1954 and TR-HCC1954 cell line respectively. Furthermore, the combination of honokiol and trastuzumab resulted in significant differences in cytotoxicity in TR-HCC1954 cells at specific concentrations. Molecular docking and the qRT-PCR showed that the potential ERα identified from the bioinformatics analysis was affected by the treatment. Our results show that honokiol has the potential to increase the sensitivity of trastuzumab in HER2+ trastuzumab resistant breast cancer cell line HCC1954 by affecting regulating estrogen receptor signaling. Further research is necessary to validate these findings. [Display omitted] •Using bioinformatics to explore the potential target hub gene of honokiol in HER2+ trastuzumab-resistant breast cancer cells.•Honokiol increased the sensitivity of trastuzumab in trastuzumab-resistant HCC1954 breast cancer cells.•ERα as the potential target of honokiol in overcoming breast cancer resistance towards trastuzumab.