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

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 se...

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Bibliographic Details
Published in:Apoptosis (London) 2022-08, Vol.27 (7-8), p.545-560
Main Authors: Sun, Yaxin, Sha, Beibei, Huang, Wenjing, Li, Miaomiao, Zhao, Shan, Zhang, Yuan, Yan, Jie, Li, Zheng, Tang, Jingwen, Duan, Peiyan, Shi, Jianxiang, Li, Pei, Hu, Tao, Chen, Ping
Format: Article
Language:English
Subjects:
Anticancer properties
Antitumor activity
Apoptosis
Autophagy
Biochemistry
Biomedical and Life Sciences
Biomedicine
Bone cancer
Breast cancer
c-Myc protein
Cancer Research
Cell Biology
Cell culture
Cell cycle
Cell growth
Cell viability
Cyclin D1
DNA damage
Drug resistance
Esophageal cancer
Esophagus
G1 phase
Inhibitors
Leukemia
Liver cancer
Medical prognosis
Multiple myeloma
Myc protein
Oncology
p53 Protein
Prostate cancer
Squamous cell carcinoma
Tumorigenesis
Tumors
Virology
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Summary: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.
ISSN:1360-8185
1573-675X
DOI:10.1007/s10495-022-01736-x