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ML323, a USP1 inhibitor triggers cell cycle arrest, apoptosis and autophagy in esophageal squamous cell carcinoma cells

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Abstract

Esophageal squamous cell carcinoma (ESCC) is a common digestive cancer with high mortality rate due to late diagnosis and drug resistance. It is important to identify new molecular target and develop new anticancer strategy. ML323 is a novel USP1 inhibitor and exhibits anticancer activity against several cancers. Herein, we investigated whether ML323 has some cytotoxity effect on ESCC cells and explored the underlying mechanisms. Results revealed that ML323 impeded esophageal cancer cell viability and colony formation. Meanwhile, ML323 blocked cells at G0/G1 phase concomitant with the reduced protein level of c-Myc, cyclin D1, CDK4 and CDK6. ML323 treatment also triggered DNA damage and active p53. Then, ML323 induced apoptosis by p53-Noxa. Additionally, it stimulated protective autophagy. Co-treatment with CQ or BafA1, two classical autophagy inhibitors, enhanced the cytotoxity of ML323. These findings suggested that USP1 inhibitor (ML323) could be used as a viable anti-ESCC approach.

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Data availability

All data generated or analyzed during this study are included in this published article.

Abbreviations

ESCC:

Esophageal squamous cell carcinoma

HCC:

Hepatocellular carcinoma

MM:

Multiple myeloma

EMT:

Epithelial-mesenchymal transition

TNBC:

Triple negative breast cancer

BafA1:

BafilomycinA1

CQ:

Chloroquine

DMSO:

Dimethyl sulfoxide

PBS:

Phosphate-buffered saline

MMP:

Mitochondrial membrane potential

AO:

Acridine orange

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Acknowledgements

This work was supported by the National Natural Science Foundation Grant of China (Grant No. 81672421), Program for Innovation Research Team (in Science and Technology) in University of Henan Province (Grant No. 20IRTSTHN026) and Open Project Fund of Henan Key Laboratory of Precision Clinical Pharmacy (Grant No. HKLPCP-2020-06).

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  1. Yaxin Sun and Beibei Sha have contributed to this work equally.

Authors and Affiliations

  1. Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China

    Yaxin Sun, Beibei Sha, Wenjing Huang, Miaomiao Li, Shan Zhao, Yuan Zhang, Jingwen Tang, Peiyan Duan, Pei Li, Tao Hu & Ping Chen

  2. Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Ping Chen

  3. The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, China

    Jie Yan & Zheng Li

  4. Precision Medicine Center, Henan Institute of Medical and Pharmaceutical Sciences &, BGI College, Zhengzhou University, Zhengzhou, 450052, China

    Jianxiang Shi

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  1. Yaxin Sun
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Contributions

Conceptualization, TH and PC; Methodology, BS, YS, SZ, ML, WH, YZ, JY, ZL, JT, and PD; Writing-Original draft preparation, BS and YS; Writing- Reviewing and Editing, JS, TH and PC; Supervision, TH and PC; Funding acquisition, PC and PL. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Tao Hu or Ping Chen.

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Sun, Y., Sha, B., Huang, W. et al. ML323, a USP1 inhibitor triggers cell cycle arrest, apoptosis and autophagy in esophageal squamous cell carcinoma cells. Apoptosis 27, 545–560 (2022). https://doi.org/10.1007/s10495-022-01736-x

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