LINCS gene expression signature analysis revealed bosutinib as a radiosensitizer of breast cancer cells by targeting eIF4G1

• Published in: International journal of molecular medicine Vol. 47; no. 5; p. 1
• Main Authors: Hu, Sai, Xie, Dafei, Zhou, Pingkun, Liu, Xiaodan, Yin, Xiaoyao, Huang, Bo, Guan, Hua
• Format: Journal Article
• Language: English
• Published: Greece Spandidos Publications 01.05.2021; Spandidos Publications UK Ltd; D.A. Spandidos
• Subjects: Analysis; Aniline Compounds - pharmacology; Apoptosis; Autophagy; Biotechnology; Bosutinib; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer cells; Cancer therapies; Cell cycle; Cell growth; Databases, Nucleic Acid; Datasets; Deoxyribonucleic acid; DNA; DNA damage; Drug dosages; Eukaryotic Initiation Factor-4G - genetics; Eukaryotic Initiation Factor-4G - metabolism; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genetic aspects; Genetic translation; Health aspects; Humans; Kinases; Medical research; Mortality; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nitriles - pharmacology; Proteins; Quinolines - pharmacology; Radiation; Radiation therapy; Radiation-Sensitizing Agents - pharmacology; Radiotherapy; Targeted cancer therapy; Transcriptome - drug effects; Beijing China; China; LINCS; eIF4G1; enrichment score; drug reposition; radiosensitization; bosutinib
• ISSN: 1107-3756; 1791-244X
• DOI: 10.3892/ijmm.2021.4905

Radioresistance is the predominant cause for radiotherapy failure and disease progression, resulting in increased breast cancer‑associated mortality. Using gene expression signature analysis of the Library of Integrated Network‑Based Cellular Signatures (LINCS) and Gene Expression Omnibus (GEO), the aim of the present study was to systematically identify potential candidate radiosensitizers from known drugs. The similarity of integrated gene expression signatures between irradiated eukaryotic translation initiation factor 4 γ 1 (eIF4G1)‑silenced breast cancer cells and known drugs was measured using enrichment scores (ES). Drugs with positive ES were selected as potential radiosensitizers. The radiosensitizing effects of the candidate drugs were analyzed in breast cancer cell lines (MCF‑7, MX‑1 and MDA‑MB‑231) using CCK‑8 and colony formation assays following exposure to ionizing radiation. Cell apoptosis was measured using flow cytometry. The expression levels of eIF4G1 and DNA damage response (DDR) proteins were analyzed by western blotting. Bosutinib was identified as a promising radiosensitizer, as its administration markedly reduced the dosage required both for the drug and for ionizing radiation, which may be associated with fewer treatment‑associated adverse reactions. Moreover, combined treatment of ionizing radiation and bosutinib significantly increased cell killing in all three cell lines, compared with ionizing radiation or bosutinib alone. Among the three cell lines, MX‑1 cells were identified as the most sensitive to both ionizing radiation and bosutinib. Bosutinib markedly downregulated the expression of eIF4G1 in a dose‑dependent manner and also reduced the expression of DDR proteins (including ATM, XRCC4, ATRIP, and GADD45A). Moreover, eIF4G1 was identified as a key target of bosutinib that may regulate DNA damage induced by ionizing radiation. Thus, bosutinib may serve as a potential candidate radiosensitizer for breast cancer therapy.