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A FOXM1-Targeted Peptide Overcomes 5-Fluorouracil Resistance via Modulating ABC Transporters in Liver Cancer HepG2 Cells

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Abstract

Drug resistance largely limits the efficacy and efficiency of chemotherapeutics, which is a first-line treatment for liver cancer, consequently triggering a complete failure in clinical application. There are numerous attempts in exploring potential strategies for avoiding drug resistance, but none of them has effectively addressed this problem. Therefore, novel molecular targets and agents proposed for addressing drug resistance are needed. This study established 5-fluorouracil (5-Fu)-resistant HepG2 cells (HepG2/R) and showed that a FOXM1-targeted peptide, P201, reactivated 5-Fu to attenuate HepG2/R cell viability, proliferation, migration and promote apoptosis. Moreover, both pharmacological studies and RNA genomic sequencing results uncovered that combination of P201 and 5-Fu notably decreased expressions of FOXM1, MDR1 and ABCG2 compared to 5-Fu alone, indicating P201 overcame 5-Fu resistance mainly through inhibiting FOXM1 and ABC transporters. Therefore, P201 could inhibit ABC transporters by targeting FOXM1 in HepG-2/R cells, overcoming 5-Fu resistance and enhancing anti-cancer drug sensitivity. FOXM1 may be a new target for overcoming 5-Fu resistance in HepG2 cell while the combination treatment of P201 and 5-Fu may serve as a potential strategy for treating liver cancer.

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Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Dr. Phang C. Tai (Regents’ Professor of Department of Biology, Georgia State University, Atlanta, GA, 30303, USA) for his helpful comments and revisions in manuscript preparation. This work was financially supported by the Key Research and Development Project of Chengdu (No. 2018-YF05-00004-SN), the National Natural Science Foundation of China (Nos. 81872789, No.82003784), Sichuan Science and Technology Program (No. 2021JDRC0145), and the Fundamental Research Funds for the Central Universities (No. 2682019CX73). The RNA sequencing and its data analysis was supported by Annoroad Gene Technology Company.

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Author notes

  1. Hongping Guo and Yuhong Jiang have contributed equally to this work and are joint first authors.

Authors and Affiliations

  1. School of Life Science and Engineering, Southwest Jiaotong University, No.111, North Section 1, Erhuan Road, Jinniu District, Chengdu, 610031, Sichuan, People’s Republic of China

    Hongping Guo, Yuhong Jiang, Zhiguang Ao, Siyi Wang & Canquan Mao

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  1. Hongping Guo
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  2. Yuhong Jiang
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  3. Zhiguang Ao
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Correspondence to Canquan Mao.

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Guo, H., Jiang, Y., Ao, Z. et al. A FOXM1-Targeted Peptide Overcomes 5-Fluorouracil Resistance via Modulating ABC Transporters in Liver Cancer HepG2 Cells. Int J Pept Res Ther 27, 1815–1826 (2021). https://doi.org/10.1007/s10989-021-10212-0

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