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Early and consistent overexpression of ADRM1 in ovarian high-grade serous carcinoma
Rosie T Jiang1, Anna Yemelyanova1, Deyin Xing1
1Department of Pathology, The Johns Hopkins University, Baltimore, MD, 21231, USA.
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.
Insights
RPN13 is a promising target for ovarian cancer treatment. The drug RA190 effectively targets RPN13 in both early and advanced ovarian cancers, regardless of ADRM1 gene amplification.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Ovarian carcinoma relies on the ubiquitin proteasome system (UPS).
- Proteasome inhibitors like bortezomib have shown limited clinical success.
- Targeting RPN13, a protein involved in UPS substrate recognition, presents an alternative strategy.
Purpose of the Study:
- To investigate RPN13 (encoded by ADRM1) as a therapeutic target in ovarian and fallopian tube cancers.
- To assess the expression of RPN13 in precursor lesions and advanced ovarian carcinoma.
- To determine the impact of ADRM1 gene amplification on ovarian cancer sensitivity to the RPN13 inhibitor RA190.
Main Methods:
- Quantification of ADRM1 mRNA using RNAscope in situ hybridization.
- Detection of RPN13 protein via immunohistochemistry in high-grade serous carcinoma (HGSC) and serous tubal intraepithelial carcinoma (STIC).
- Assessment of ADRM1 amplification and RA190 sensitivity in ovarian cancer cell lines.
Main Results:
- ADRM1 mRNA expression was significantly elevated in STIC and HGSC compared to normal fallopian tube epithelium.
- RPN13 was ubiquitously and robustly expressed in ovarian carcinoma tissues and cell lines.
- Ovarian cancer cell lines demonstrated sensitivity to RA190 irrespective of ADRM1 gene amplification status.
Conclusions:
- RPN13 is a viable therapeutic target for both in situ and metastatic ovarian carcinoma.
- The RPN13 inhibitor RA190 shows potential for treating ovarian cancers.
- Ovarian cancer cell sensitivity to RA190 is not dependent on ADRM1 gene amplification.
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