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J Ovarian Res. 2017 Aug 7;10(1):53. doi: 10.1186/s13048-017-0347-y.

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

Author information

1
Department of Pathology, The Johns Hopkins University, Baltimore, MD, 21231, USA.
2
Department of Oncology, The Johns Hopkins University, Baltimore, MD, 21231, USA.
3
Laboratory of Protein Metabolism, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
4
Division of Molecular Genetics and Pathology, Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD, 20993, USA.
5
Division of Gynecologic Pathology, The Johns Hopkins University, Baltimore, MD, 21231, USA.
6
Department of Pathology, The Johns Hopkins University, Baltimore, MD, 21231, USA. roden@jhmi.edu.
7
Department of Oncology, The Johns Hopkins University, Baltimore, MD, 21231, USA. roden@jhmi.edu.
8
Departments of Gynecology and Obstetrics, The Johns Hopkins University, Baltimore, MD, 21231, USA. roden@jhmi.edu.

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.

KEYWORDS:

ADRM1; Ovarian/fallopian tube cancer; Proteasome inhibitor; RPN13; STIC

PMID:
28784174
PMCID:
PMC5547474
DOI:
10.1186/s13048-017-0347-y
[Indexed for MEDLINE]
Free PMC Article

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