1. Academic Validation
  2. ML323, a USP1 inhibitor triggers cell cycle arrest, apoptosis and autophagy in esophageal squamous cell carcinoma cells

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

  • Apoptosis. 2022 Aug;27(7-8):545-560. doi: 10.1007/s10495-022-01736-x.
Yaxin Sun  # 1 Beibei Sha  # 1 Wenjing Huang 1 Miaomiao Li 1 Shan Zhao 1 Yuan Zhang 1 Jie Yan 2 Zheng Li 2 Jingwen Tang 1 Peiyan Duan 1 Jianxiang Shi 3 Pei Li 1 Tao Hu 4 Ping Chen 5 6
Affiliations

Affiliations

  • 1 Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
  • 2 The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, China.
  • 3 Precision Medicine Center, Henan Institute of Medical and Pharmaceutical Sciences &, BGI College, Zhengzhou University, Zhengzhou, 450052, China.
  • 4 Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. [email protected].
  • 5 Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. [email protected].
  • 6 Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. [email protected].
  • # Contributed equally.
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.

Keywords

Apoptosis; Autophagy; Cell cycle arrest; Esophageal squamous cell carcinoma; ML323.

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