The proteasome deubiquitinase inhibitor bAP15 downregulates TGF-β/Smad signaling and induces apoptosis via UCHL5 inhibition in ovarian cancer
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Shiho Fukui1, Kazunori Nagasaka1, Yuko Miyagawa1, Ryoko Kikuchi-Koike1, Yoshiko Kawata2, Ranka Kanda1, Takayuki Ichinose1, Takeru Sugihara1, Haruko Hiraike1, Osamu Wada-Hiraike2, Yuko Sasajima3 and Takuya Ayabe1
1 Department of Obstetrics and Gynecology, Teikyo University School of Medicine, Itabashi-ku, Tokyo 173-8605, Japan
2 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
3 Department of Pathology, Teikyo University School of Medicine, Itabashi-ku, Tokyo 173-8605, Japan
|Kazunori Nagasaka,||email:||[email protected]|
Keywords: ovarian cancer; bAP15; TGF-β/Smad signaling; UCHL5; apoptosis
Received: May 13, 2019 Accepted: September 10, 2019 Published: October 15, 2019
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 TP53 mutations was significantly more likely to exhibit poor PFS (p <0.001). Moreover, we found bAP15 could suppress TP53-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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