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bioRxiv · 10.1101/2020.04.24.059378

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

Hu, S.·Zhou, P.·Liu, X.·Yin, X.·XIE, D.·Huang, B.·Guan, H.
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Abstract

Radioresistance represents the predominant cause for radiotherapy failure and disease progression, resulting in increased breast cancer mortality. Through gene expression signatures analyses of Library of Integrated Network-Based Cellular Signatures (LINCS) and Gene Expression Omnibus (GEO), the present study aimed to identify potential candidate radiosensitizers from known drugs systematically. The similarity of integrated gene expression signatures between irradiated eIF4G1-silenced breast cancer cells and known drugs was measured by enrichment scores. Drugs with positive enrichment scores were selected as potential radiosensitizers. The radiosensitizing effects of the candidate radiosensitizers were analyzed in breast cancer cells (MCF-7, MX-1, and MDA-MB-231) by CCK-8 assays and colony-forming capability after exposure to ionizing radiation. Cell apoptosis was detected by flow cytometry. Expressions of eIF4G1 and a series of DNA damage response proteins were analyzed by Western blot assays. Bosutinib was proposed to be a promising radiosensitizer as its administration markedly reduced the dosages of both the drug and ionizing radiation and was associated with fewer adverse drug reactions. The combined treatment with ionizing radiation and bosutinib significantly increased the cells killing potency in all three cell lines as compared to ionizing radiation or bosutinib alone. MX-1 cells were revealed to be the most sensitive to both ionizing radiation and bosutinib among the three cell lines. Bosutinib noticeably downregulated the expression of eIF4G1 in a dose-dependent manner and also reduced the expression of DNA damage response proteins (including ATM, XRCC4, ATRIP, and GADD45a). Moreover, eIF4G1 could be a key target of bosutinib through which it regulates DNA damage induced by ionizing radiation. Thus, taken together, bosutinib may serve as a potential candidate radiosensitizer for breast cancer therapy.

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Hu, S., Zhou, P., Liu, X., Yin, X., XIE, D., Huang, B., Guan, H.. 2020-04-24. LINCS gene expression signatures analysis revealed bosutinib as a radiosensitizer of breast cancer cells by targeting eIF4G1. https://doi.org/10.1101/2020.04.24.059378

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