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 Ca²⁺ 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 Ca²⁺ and then stimulated autophagy through Ca²⁺‐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.

Aim: The aim of our study was to explore the role of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) on the exposure of SiO2 nanoparticles (NPs) and its influence. Materials & methods: To understand the mechanism of NP-induced oxidative stress, the involvement of oxidative-stress-responding transcription factors and the Nrf2/antioxidant reactive element (ARE) signaling pathway in the toxicity of SiO2 NPs’ exposure was investigated via in vivo and in vitro models. Results: A549 cells showed a significant cytotoxic effect while A549-shNrf2 cells showed decreased cell viability after nm-SiO2 exposure. SiO2 NPs’ exposure activated the Nrf2/ARE signaling pathway. Nrf2−/− exposed mice showed increased reactive oxygen species, 8-hydroxyl deoxyguanosine level and decreased total antioxidant capacity. Nrf2/ARE signaling pathway activation disrupted, leading inhibition of heme oxygenase-1 and upregulation of PKR-like endoplasmic-reticulum-regulated kinase. Conclusion: Our findings suggested that Nrf2 cou...

Low glucose is a common microenvironment for rapidly growing solid tumors, which has developed multiple approaches to survive under glucose deprivation. However, the specific regulatory mechanism remains largely elusive. In this study, we demonstrate that glucose deprivation, while not amino acid or serum starvation, transactivates the expression of DCAF1. This enhances the K48-linked polyubiquitination and proteasome-dependent degradation of Rheb, inhibits mTORC1 activity, induces autophagy, and facilitates cancer cell survival under glucose deprivation conditions. This study identified DCAF1 as a new cellular glucose sensor and uncovered new insights into mechanism of DCAF1-mediated inactivation of Rheb-mTORC1 pathway for promoting cancer cell survival in response to glucose deprivation.