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Journal of Ovarian Research
Published in: Journal of Ovarian Research 1/2017

Open Access 01-12-2017 | Research

Early and consistent overexpression of ADRM1 in ovarian high-grade serous carcinoma

Authors: Rosie T. Jiang, Anna Yemelyanova, Deyin Xing, Ravi K. Anchoori, Jun Hamazaki, Shigeo Murata, Jeffrey D. Seidman, Tian-Li Wang, Richard B. S. Roden

Published in: Journal of Ovarian Research | Issue 1/2017

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Abstract

Background

Ovarian carcinoma is highly dependent on the ubiquitin proteasome system (UPS), but its clinical response to treatment with the proteasome inhibitor bortezomib has been disappointing. This has driven exploration of alternate approaches to target the UPS in ovarian cancer. Recently, proteasome inhibitors targeting the 19S regulatory particle-associated RPN13 protein have been described, such as RA190. RPN13, which is encoded by ADRM1, facilitates the recognition by the proteasome of its polyubiquinated substrates. Inhibition of RPN13 produces a rapid, toxic accumulation of polyubiquitinated proteins in ovarian and other cancer cells, triggering apoptosis.
Here, we sought to determine if RPN13 is available as a target in precursors of ovarian/fallopian tube cancer as well as all advanced cases, and the impact of increased ADRM1 gene copy number on sensitivity of ovarian cancer to RA190.

Methods

ADRM1 mRNA was quantified by RNAscope in situ hybridization and RPN13 protein detected by immunohistochemistry in high grade serous carcinoma (HGSC) of the ovary and serous tubal intraepithelial carcinoma (STIC). Amplification of ADRM1 and sensitivity to RA190 were determined in ovarian cancer cell lines.

Results

Here, we demonstrate that expression of ADRM1mRNA is significantly elevated in STIC and HGSC as compared to normal fallopian tube epithelium. ADRM1 mRNA and RPN13 were ubiquitously and robustly expressed in ovarian carcinoma tissue and cell lines. No correlation was found between ADRM1 amplification and sensitivity of ovarian cancer cell lines to RA190, but all were susceptible.

Conclusions

RPN13 can potentially be targeted by RA190 in both in situ and metastatic ovarian carcinoma. Ovarian cancer cell lines are sensitive to RA190 regardless of whether the ADRM1 gene is amplified.
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Metadata
Title
Early and consistent overexpression of ADRM1 in ovarian high-grade serous carcinoma
Authors
Rosie T. Jiang
Anna Yemelyanova
Deyin Xing
Ravi K. Anchoori
Jun Hamazaki
Shigeo Murata
Jeffrey D. Seidman
Tian-Li Wang
Richard B. S. Roden
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Ovarian Research / Issue 1/2017
Electronic ISSN: 1757-2215
DOI
https://doi.org/10.1186/s13048-017-0347-y

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