Inhibition of USP2 Enhances TRAIL-Mediated Cancer Cell Death through Downregulation of Survivin

Ubiquitin-specific protease 2 (USP2) is a deubiquitinase belonging to the USPs subfamily. USP2 has been known to display various biological effects including tumorigenesis and inflammation. Therefore, we aimed to examine the sensitization effect of USP2 in TRAIL-mediated apoptosis. The pharmacological inhibitor (ML364) and siRNA targeting USP2 enhanced TNF-related apoptosis-inducing ligand (TRAIL)-induced cancer cell death, but not normal cells. Mechanistically, USP2 interacted with survivin, and ML364 degraded survivin protein expression by increasing the ubiquitination of survivin. Overexpression of survivin or USP2 significantly prevented apoptosis through cotreatment with ML364 and TRAIL, whereas a knockdown of USP2 increased sensitivity to TRAIL. Taken together, our data suggested that ML364 ubiquitylates and degrades survivin, thereby increasing the reactivity to TRAIL-mediated apoptosis in cancer cells.

 

Comments:

It sounds like your research focuses on investigating the role of Ubiquitin-specific protease 2 (USP2) in regulating TRAIL-mediated apoptosis in cancer cells. Here's a breakdown of your findings:

1. **USP2 and TRAIL Sensitization:** The study aimed to explore how USP2 affects cancer cells' sensitivity to TRAIL-induced apoptosis. Both a pharmacological inhibitor (ML364) and siRNA targeting USP2 were found to enhance TRAIL-induced cancer cell death without affecting normal cells.

2. **Mechanism Involving Survivin:** The research identified an interaction between USP2 and survivin. ML364, the inhibitor of USP2, led to the degradation of survivin by increasing its ubiquitination.

3. **Survivin's Role in Apoptosis:** Overexpression of survivin or USP2 significantly prevented apoptosis when cancer cells were treated with ML364 and TRAIL together. Conversely, knocking down USP2 increased the sensitivity of cancer cells to TRAIL-induced apoptosis.

4. **Conclusion:** The data suggests that ML364 induces the ubiquitination and subsequent degradation of survivin, leading to increased susceptibility of cancer cells to TRAIL-mediated apoptosis.

This research holds promise in understanding the intricate mechanisms involved in regulating apoptosis in cancer cells and potentially opens avenues for targeted therapies aiming to enhance cancer cell death through TRAIL induction.

Related Products

Cat.No.	Product Name	Information
S6748	ML364	ML364 is a small molecule inhibitor of the deubiquitinase USP2 with an IC50 of 1.1 μM in a biochemical assay using an internally quenched fluorescent di-ubiquitin substrate.

Related Targets

DUB