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Cellular and Molecular Biology

ULK1 promotes oxaliplatin resistance of colon cancer via phosphorylation of Bax S184

British Journal of Cancer (2026)Cite this article

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Abstract

Background

Oxaliplatin resistance continues to undermine therapeutic outcomes in colon cancer (CC). Recent investigations point to unc-51 like kinase 1 (ULK1)-mediated disruption of apoptotic pathways as a potential driver of chemoresistance, though the exact mechanisms remain incompletely characterized.

Methods

Using established CC cell lines, we developed oxaliplatin-resistant models through stepwise dose escalation. ULK1 expression was modulated through targeted siRNA knockdown and stable overexpression. Protein interactions were examined via co-immunoprecipitation coupled with mass spectrometry, supplemented by kinase activity assays. Functional impact was assessed through proliferation kinetics, apoptosis profiling, and tumor xenograft studies. Clinical correlations were derived from TCGA analysis and immunohistochemical evaluation of patient tumor specimens.

Results

ULK1 overexpression consistently correlated with oxaliplatin resistance and adverse clinical parameters. At the molecular level, ULK1 catalyzed Bcl-2 associated X protein (Bax) phosphorylation at Ser184, creating a recognition motif for Parkin-mediated ubiquitination and proteasomal targeting. Disruption of this axis through ULK1 inhibition restored Bax protein levels, enhanced apoptotic response, and reversed oxaliplatin resistance in both cellular and animal models.

Conclusion

These findings identify ULK1-dependent phosphorylation as a novel regulatory mechanism governing Bax stability in CC. The study provides preclinical rationale for targeting the ULK1-Bax interface to overcome oxaliplatin resistance, while highlighting the need for further investigation into optimal therapeutic strategies.

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Fig. 1: ULK1 is elevated in oxaliplatin-resistance colon cancer cells.
Fig. 2: The effect of Ulk1 on Oxaliplatin-induced apoptosis of CC cells.
Fig. 3: ULK1 could interact with Bax.
Fig. 4: Oxaliplatin triggers the degradation of Bax through the ULK1-induced phosphorylation on Ser184 to inhibit the apoptosis of CC cells.
Fig. 5: Persistent phosphorylation of Bax 184 inhibits apoptosis in oxaliplatin-resistant cell lines of colon cancer.
Fig. 6: Suppression of ULK1-mediated Bax-Ser184 phosphorylation improves efficacy of Oxaliplatin on CC.

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Data availability

All data analysed during this study are included in this published article.

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Acknowledgements

Thanks for the technical support of confocal laser scanning microscope (LEICA TCS SP8) and flow cytometer (BECKMAN CytoFlex S) by the Core Facilities (Disen Mei, meidisen@nbu.edu.cn; Danhong Wan, wandanhong@nbu.edu.cn), Health Science Center, Ningbo University. We also thank Chao Dong, Mengjie Yang and Xiqin Guo from the Laboratory Animal Center of Ningbo University for their technical support.

Funding

This study is partly supported by Zhejiang Provincial Natural Science Foundation of China under Grant no.MS26H160044(JC) and LY24C050001(XJ).The National Natural Science Foundation of China grant no. 32270821 (XJ) and 32570835(XJ). The Natural Science Foundation of Ningbo grant no. 2024J037 (XJ) and 2024J413(CJ). The KC Wong Magna Fund in Ningbo University (XJ). The Zhejiang Provincial Medical and Health Science and Technology Plan grant no.2025KY1472 (JC). The Wu Jieping Medical Foundation grant no.320.6750.2022-22-33.

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Author notes

  1. These authors contributed equally: Ze Rong, Jing Xing.

Authors and Affiliations

  1. Department of Chemoradiotherapy, the Affiliated People’s Hospital of Ningbo University, Ningbo, China

    Ze Rong, Jing Xing, Liangpei Wu, Kaifeng Zheng, Linrong Pang, Jun Chen & Xiaofeng Jin

  2. Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, China

    Xiaofeng Jin

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  1. Ze Rong
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  2. Jing Xing
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Contributions

Conceptualization, ZR and JX; Investigation, ZR, JX, and KFZ; Writing - Original Draft, LP and JX; Writing - Review & Editing, LRP, JC, and XFJ; Supervision, XFJ and JC; Visualization, JX and ZR. The version of the manuscript for publication has been read and is in agreement with all authors.

Corresponding authors

Correspondence to Jun Chen or Xiaofeng Jin.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

CC specimens and paired adjacent normal tissues of human patients were collected from the Yinzhou People’s Hospital after obtaining written consent from the patients. All experimental procedures involving patients were conducted in accordance with the ethical guidelines of the Declaration of Helsinki and were approved by the Ethics Committee of Yinzhou People’s Hospital (No. NBU-2023-213). All animal experimental procedures were approved by the Animal Care and Use Committee of the Ningbo University (No. 12530).

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Rong, Z., Xing, J., Wu, L. et al. ULK1 promotes oxaliplatin resistance of colon cancer via phosphorylation of Bax S184. Br J Cancer (2026). https://doi.org/10.1038/s41416-025-03223-x

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