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The proteasome deubiquitinase inhibitor bAP15 downregulates TGF-β/Smad signaling and induces apoptosis UCHL5 inhibition in ovarian cancer. | LitMetric

AI Article Synopsis

  • The ubiquitin-proteasome pathway is crucial for regulating cellular proteins, and recent studies are identifying deubiquitinating enzymes (DUBs) as new targets for cancer therapies, especially in breast, endometrial, and prostate cancers, as well as multiple myeloma.
  • Research shows that the DUB inhibitor bAP15 can inhibit cell growth in various cancers; however, its mechanism in ovarian cancer is still not fully understood.
  • In a study involving 1,435 ovarian cancer patients, high UCHL5 expression was linked to shorter progression-free survival, and bAP15 was found to induce cancer cell death by affecting TGF-β signaling, suggesting UCHL5 inhibition could be a promising

Article Abstract

The ubiquitin-proteasome pathway plays an important role in the regulation of cellular proteins. As an alternative to the proteasome itself, recent research has focused on methods to modulate the regulation of deubiquitinating enzymes (DUBs) upstream of the proteasome, identifying DUBs as novel therapeutic targets in breast, endometrial, and prostate cancers, along with multiple myeloma. bAP15, an inhibitor of the 19S proteasome DUBs UCHL5 and USP14, results in cell growth inhibition in several human cancers; however, the mechanism remains poorly understood in ovarian cancer. Here, we found that aberrant UCHL5 expression predicted shorter progression-free survival (PFS) in a cohort of 1435 patients with ovarian cancer described in the Gene Expression Omnibus and The Cancer Genome Atlas databases. The subgroup of patients with mutations was significantly more likely to exhibit poor PFS ( <0.001). Moreover, we found bAP15 could suppress -mutant ovarian cancer cell survival by regulating TGF-β signaling through inhibiting UCHL5 expression and dephosphorylating Smad2, consequently inducing apoptosis. bAP15 (2.5 and 5.0 mg/kg) also exerted significant anti-tumor effect on nude mice bearing subcutaneous SKOV3 xenografts. As activated TGF-β signaling is involved in ovarian cancer progression, these findings suggest that UCHL5 inhibition offers potential opportunities for a novel targeted therapy against TGF-β-activated ovarian cancer.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800272PMC
http://dx.doi.org/10.18632/oncotarget.27219DOI Listing

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