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

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

Research output: Contribution to journalReview article

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.

Original languageEnglish (US)
Article number53
JournalJournal of Ovarian Research
Volume10
Issue number1
DOIs
StatePublished - Aug 7 2017

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Ovarian Neoplasms
Carcinoma
Proteasome Endopeptidase Complex
Cell Line
Proteasome Inhibitors
Carcinoma in Situ
Ubiquitin
Fallopian Tube Neoplasms
Messenger RNA
Proteins
Gene Dosage
Fallopian Tubes
Poisons
In Situ Hybridization
Ovary
Epithelium
Immunohistochemistry
Apoptosis
Genes

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

Cite this

Early and consistent overexpression of ADRM1 in ovarian high-grade serous carcinoma. / Jiang, Rosie T.; Yemelyanova, Anna; Xing, Deyin; Anchoori, Ravi; Hamazaki, Jun; Murata, Shigeo; Seidman, Jeffrey D.; Wang, Tian-Li; Roden, Richard S.

In: Journal of Ovarian Research, Vol. 10, No. 1, 53, 07.08.2017.

Research output: Contribution to journalReview article

Jiang, Rosie T. ; Yemelyanova, Anna ; Xing, Deyin ; Anchoori, Ravi ; Hamazaki, Jun ; Murata, Shigeo ; Seidman, Jeffrey D. ; Wang, Tian-Li ; Roden, Richard S. / Early and consistent overexpression of ADRM1 in ovarian high-grade serous carcinoma. In: Journal of Ovarian Research. 2017 ; Vol. 10, No. 1.
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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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T1 - Early and consistent overexpression of ADRM1 in ovarian high-grade serous carcinoma

AU - Jiang, Rosie T.

AU - Yemelyanova, Anna

AU - Xing, Deyin

AU - Anchoori, Ravi

AU - Hamazaki, Jun

AU - Murata, Shigeo

AU - Seidman, Jeffrey D.

AU - Wang, Tian-Li

AU - Roden, Richard S

PY - 2017/8/7

Y1 - 2017/8/7

N2 - 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.

AB - 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.

KW - ADRM1

KW - Ovarian/fallopian tube cancer

KW - Proteasome inhibitor

KW - RPN13

KW - STIC

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U2 - 10.1186/s13048-017-0347-y

DO - 10.1186/s13048-017-0347-y

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