Skip to main content
  • AACR Publications
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

  • Register
  • Log in
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Focus on Computer Resources
    • 75th Anniversary
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citations
    • Author/Keyword
  • News
    • Cancer Discovery News
  • AACR Publications
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in

Search

  • Advanced search
Cancer Research
Cancer Research

Advanced Search

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Focus on Computer Resources
    • 75th Anniversary
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citations
    • Author/Keyword
  • News
    • Cancer Discovery News
Experimental and Molecular Therapeutics

Abstract 3068: Proteotoxic stress associated with mTORC1 activation in ovarian carcinoma: proteasome inhibition as a therapeutic strategy

M. Herman Chui, Patricia Shaw and Robert Rottapel
M. Herman Chui
University of Toronto, Toronto, Ontario, Canada.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Patricia Shaw
University of Toronto, Toronto, Ontario, Canada.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert Rottapel
University of Toronto, Toronto, Ontario, Canada.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1538-7445.AM2017-3068 Published July 2017
  • Article
  • Info & Metrics
Loading
Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC

Abstract

Genetic profiling studies of high grade serous ovarian carcinoma have revealed recurrent alterations in the mTORC1 signalling network (e.g. mutations/copy number alterations in PTEN, TSC1, TSC2, and PIK3CA) and pathway activation, detected by phospho-4E-BP1, has been associated with poor prognosis. We sought to characterize functionally the role of mTORC1 signalling and its therapeutic implications in ovarian cancer. Treatment of ovarian cancer cell lines with rapamycin resulted in inhibition of mTORC1 signalling and decreased rate of protein synthesis. However, irrespective of PTEN mutation status, only mild cytostatic effects were achieved even with high concentrations of rapamycin. We next examined the phenotypic consequences of mTOR activation, using siRNA directed against TSC2. Surprisingly, we observed striking growth inhibition in the majority of ovarian cancer cell lines, whether grown under adherent monolayer culture or in 3-dimensional spheroid culture conditions. While mTORC1 pathway activation was confirmed biochemically, knockdown of TSC2 also resulted in activation of the unfolded protein response (UPR), with elevated levels of phospho-EIF2α and ATF4, consistent with the accumulation of misfolded proteins in the endoplasmic reticulum.

From a therapeutic standpoint, the resulting burden on the ubiquitin-proteasome system should render these cells particularly sensitive to proteasome inhibition. We show that treatment with the proteasome inhibitor, bortezomib, causes increased accumulation of detergent-insoluble poly-ubiquinated proteins and formation of larger and more abundant cytoplasmic protein aggregates in siTSC2-transfected compared to scrambled siRNA-transfected ovarian carcinoma cells. This was accompanied by a more pronounced UPR stress response, including induction of pro-apoptotic CHOP, and suppression of autophagy, resulting in marked cytotoxicity. Conversely, we show that inhibition of protein synthesis by cycloheximide renders tumor cells resistant to bortezomib. Increased resistance to bortezomib was also noted when cells were grown as spheroids, a condition associated with suppression of mTORC1 signalling and decreased protein synthesis. This resistant phenotype of tumour spheroids however was ameliorated with TSC2 knockdown. Our findings demonstrate that protein homeostasis is finely-tuned in ovarian cancer and that mutations in mTORC1 pathway components do not necessarily imply “oncogene addiction”. In early-stage clinical trials, bortezomib has achieved notable responses in a few patients. Ovarian carcinomas with genetic alterations causing increased mTORC1 signalling may be particularly amenable to treatment with proteasome inhibitors.

Citation Format: M. Herman Chui, Patricia Shaw, Robert Rottapel. Proteotoxic stress associated with mTORC1 activation in ovarian carcinoma: proteasome inhibition as a therapeutic strategy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3068. doi:10.1158/1538-7445.AM2017-3068

  • ©2017 American Association for Cancer Research.
Previous
Back to top
Cancer Research: 77 (13 Supplement)
July 2017
Volume 77, Issue 13 Supplement
  • Table of Contents
  • Index by Author

Sign up for alerts

Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Research article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Abstract 3068: Proteotoxic stress associated with mTORC1 activation in ovarian carcinoma: proteasome inhibition as a therapeutic strategy
(Your Name) has forwarded a page to you from Cancer Research
(Your Name) thought you would be interested in this article in Cancer Research.
Citation Tools
Abstract 3068: Proteotoxic stress associated with mTORC1 activation in ovarian carcinoma: proteasome inhibition as a therapeutic strategy
M. Herman Chui, Patricia Shaw and Robert Rottapel
Cancer Res July 1 2017 (77) (13 Supplement) 3068; DOI: 10.1158/1538-7445.AM2017-3068

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Abstract 3068: Proteotoxic stress associated with mTORC1 activation in ovarian carcinoma: proteasome inhibition as a therapeutic strategy
M. Herman Chui, Patricia Shaw and Robert Rottapel
Cancer Res July 1 2017 (77) (13 Supplement) 3068; DOI: 10.1158/1538-7445.AM2017-3068
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
  • Info & Metrics
Advertisement

Related Articles

Cited By...

More in this TOC Section

Experimental and Molecular Therapeutics

  • Abstract SY14-03: Anaplastic lymphoma kinase (ALK): Normal biology and role in hematopoietic malignancies
  • Abstract SY18-01: Targeting the p53-MDM2 interaction for cancer therapy
  • Abstract SSY01-04: Discovery and validation of genome-wide genetic signatures of chemotherapy susceptibility: A translational model
Show more 3

Poster Presentations - Proffered Abstracts

  • Abstract LB-236: Risk of tMDS/AML after chemotherapy for first primary lymphoid malignancy, 2000-2013
  • Abstract LB-001: Impact of direct physician engagement with racial/ethnic minorities for oncology clinical trial access and accrual model
  • Abstract LB-107: EV-TRACK: transparent reporting and centralizing knowledge of extracellular vesicles to support the validation of extracellular vesicle biomarkers in cancer research
Show more 3

Poster Presentations - Determinants of Drug Sensitivity and Resistance

  • Abstract 3070: Lenalidomide and SMAC mimetic LCL161 show combination activity in cells harboring loss of chromosome 5q
  • Abstract 3074: Selective lethality of cisplatin in pancreatic cancer is dependent on mitotic functions of BRCA2
  • Abstract 3073: Potential predictive biomarkers of clinical responses for a novel CDC7-selective inhibitor TAK-931
Show more 3
  • Home
  • Alerts
  • Feedback
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • Meeting Abstracts

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians
  • Reviewers

About Cancer Research

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2018 by the American Association for Cancer Research.

Cancer Research Online ISSN: 1538-7445
Cancer Research Print ISSN: 0008-5472
Journal of Cancer Research ISSN: 0099-7013
American Journal of Cancer ISSN: 0099-7374

Advertisement