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Objectives: Targeting the deubiquitinases (DUBs) has become a promising avenue for anti-cancer drug development. However, the effect and mechanism of pan-DUB inhibitor, PR-619, on oesophageal squamous cell carcinoma (ESCC) cells remain to be investigated., Materials and Methods: The effect of PR-619 on ESCC cell growth and cell cycle was evaluated by CCK-8 and PI staining. Annexin V-FITC/PI double staining was performed to detect apoptosis. LC3 immunofluorescence and acridine orange staining were applied to examine autophagy. Intercellular Ca 2+ concentration was monitored by Fluo-3AM fluorescence. The accumulation of ubi-proteins and the expression of the endoplasmic reticulum (ER) stress-related protein and CaMKKβ-AMPK signalling were determined by immunoblotting., Results: PR-619 could inhibit ESCC cell growth and induce G2/M cell cycle arrest by downregulating cyclin B1 and upregulating p21. Meanwhile, PR-619 led to the accumulation of ubiquitylated proteins, induced ER stress and triggered apoptosis by the ATF4-Noxa axis. Moreover, the ER stress increased cytoplasmic Ca 2+ and then stimulated autophagy through Ca 2+ -CaMKKβ-AMPK signalling pathway. Ubiquitin E1 inhibitor, PYR-41, could reduce the accumulation of ubi-proteins and alleviate ER stress, G2/M cell cycle arrest, apoptosis and autophagy in PR-619-treated ESCC cells. Furthermore, blocking autophagy by chloroquine or bafilomycin A1 enhanced the cell growth inhibition effect and apoptosis induced by PR-619., Conclusions: Our findings reveal an unrecognized mechanism for the cytotoxic effects of general DUBs inhibitor (PR-619) and imply that targeting DUBs may be a potential anti-ESCC strategy., (© 2020 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.)

A series of novel β-carboline derivatives was designed, synthesized and evaluated as potential anticancer agents. Among them, compound 6g showed the most potent antiproliferative activity against the 786–0, HT-29 and 22RV1 cell lines with IC 50 values of 2.71, 2.02, and 3.86 μM, respectively. The antitumor efficiency of compound 6g in vivo was also evaluated, and the results revealed that compound 6g significantly suppressed tumor development and reduced tumor weight in a mouse colorectal cancer homograft model. Further investigation on mechanisms of action demonstrated that compound 6g inhibited HCT116 cell growth by stimulating the ATG5/ATG7-dependent autophagic pathway. These molecules might be served as candidates for further development of colorectal cancer therapy agent. A series of novel β-carbolines was synthesized and evaluated as potential antitumor agents. Compound 6g effectively inhibited tumor growth in BALB/c mice by triggering an autophagy pathway dependent on ATG5/ATG7. [Display omitted] • A series of novel β-carbolines was prepared and evaluated as potential antitumor agents. • Compound 6g was found to be the most potent antitumor agent in vitro. • Compound 6g significantly suppressed tumor development and reduced tumor weight in animal model. • Compound 6g inhibited HCT116 growth by stimulating the ATG5/ATG7-dependent autophagic pathway. [ABSTRACT FROM AUTHOR]