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

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Focus on Radiation Oncology
      • Novel Combinations
      • Reviews
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

  • AACR Journals
    • Blood Cancer Discovery
    • 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
  • My Cart

Search

  • Advanced search
Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Focus on Radiation Oncology
      • Novel Combinations
      • Reviews
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

Cancer Biology and Translational Studies

Inhibition of Lysosomal Function Mitigates Protective Mitophagy and Augments Ceramide Nanoliposome–Induced Cell Death in Head and Neck Squamous Cell Carcinoma

Jeremy J.P. Shaw, Timothy L. Boyer, Emily Venner, Patrick J. Beck, Tristen Slamowitz, Tara Caste, Alexandra Hickman, Michael H. Raymond, Pedro Costa-Pinheiro, Mark J. Jameson, Todd E. Fox and Mark Kester
Jeremy J.P. Shaw
1Department of Pathology, University of Virginia, Charlottesville, Virginia.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jeremy J.P. Shaw
Timothy L. Boyer
2Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Timothy L. Boyer
Emily Venner
3Department of Biology, University of Virginia, Charlottesville, Virginia.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Emily Venner
Patrick J. Beck
2Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tristen Slamowitz
2Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tara Caste
2Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alexandra Hickman
2Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael H. Raymond
4Neuroscience Graduate Program, University of Virginia, Charlottesville, Virginia.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pedro Costa-Pinheiro
1Department of Pathology, University of Virginia, Charlottesville, Virginia.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Pedro Costa-Pinheiro
Mark J. Jameson
5Department of Otolaryngology–Head and Neck Surgery, University of Virginia, Charlottesville, Virginia.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Mark J. Jameson
Todd E. Fox
6Department of Pharmacology, University of Virginia, Charlottesville, Virginia.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Todd E. Fox
Mark Kester
2Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia.
6Department of Pharmacology, University of Virginia, Charlottesville, Virginia.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: mkester@virginia.edu
DOI: 10.1158/1535-7163.MCT-20-0182 Published December 2020
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

This article requires a subscription to view the full text. You may purchase access to this article or login to access your subscription using the links below.

Abstract

Therapies for head and neck squamous cell carcinoma (HNSCC) are, at best, moderately effective, underscoring the need for new therapeutic strategies. Ceramide treatment leads to cell death as a consequence of mitochondrial damage by generating oxidative stress and causing mitochondrial permeability. However, HNSCC cells are able to resist cell death through mitochondria repair via mitophagy. Through the use of the C6-ceramide nanoliposome (CNL) to deliver therapeutic levels of bioactive ceramide, we demonstrate that the effects of CNL are mitigated in drug-resistant HNSCC via an autophagic/mitophagic response. We also demonstrate that inhibitors of lysosomal function, including chloroquine (CQ), significantly augment CNL-induced death in HNSCC cell lines. Mechanistically, the combination of CQ and CNL results in dysfunctional lysosomal processing of damaged mitochondria. We further demonstrate that exogenous addition of methyl pyruvate rescues cells from CNL + CQ–dependent cell death by restoring mitochondrial functionality via the reduction of CNL- and CQ-induced generation of reactive oxygen species and mitochondria permeability. Taken together, inhibition of late-stage protective autophagy/mitophagy augments the efficacy of CNL through preventing mitochondrial repair. Moreover, the combination of inhibitors of lysosomal function with CNL may provide an efficacious treatment modality for HNSCC.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:2621–33

  • Received March 16, 2020.
  • Revision received July 3, 2020.
  • Accepted September 28, 2020.
  • Published first October 21, 2020.
  • ©2020 American Association for Cancer Research.
View Full Text

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top
Molecular Cancer Therapeutics: 19 (12)
December 2020
Volume 19, Issue 12
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Editorial Board (PDF)

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Cancer Therapeutics 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.
Inhibition of Lysosomal Function Mitigates Protective Mitophagy and Augments Ceramide Nanoliposome–Induced Cell Death in Head and Neck Squamous Cell Carcinoma
(Your Name) has forwarded a page to you from Molecular Cancer Therapeutics
(Your Name) thought you would be interested in this article in Molecular Cancer Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Inhibition of Lysosomal Function Mitigates Protective Mitophagy and Augments Ceramide Nanoliposome–Induced Cell Death in Head and Neck Squamous Cell Carcinoma
Jeremy J.P. Shaw, Timothy L. Boyer, Emily Venner, Patrick J. Beck, Tristen Slamowitz, Tara Caste, Alexandra Hickman, Michael H. Raymond, Pedro Costa-Pinheiro, Mark J. Jameson, Todd E. Fox and Mark Kester
Mol Cancer Ther December 1 2020 (19) (12) 2621-2633; DOI: 10.1158/1535-7163.MCT-20-0182

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Inhibition of Lysosomal Function Mitigates Protective Mitophagy and Augments Ceramide Nanoliposome–Induced Cell Death in Head and Neck Squamous Cell Carcinoma
Jeremy J.P. Shaw, Timothy L. Boyer, Emily Venner, Patrick J. Beck, Tristen Slamowitz, Tara Caste, Alexandra Hickman, Michael H. Raymond, Pedro Costa-Pinheiro, Mark J. Jameson, Todd E. Fox and Mark Kester
Mol Cancer Ther December 1 2020 (19) (12) 2621-2633; DOI: 10.1158/1535-7163.MCT-20-0182
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
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Disclosure of Potential Conflicts of Interest
    • Disclaimer
    • Authors' Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • CF33 Viroimmunotherapy Cross-Primes T Cells in Colon Cancer
  • Hsp90 Inhibition and PD-1 Blockade
  • IOX1 Inhibits Oncogenic Wnt Signaling through KDM3
Show more Cancer Biology and Translational Studies
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

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

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About MCT

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

Copyright © 2021 by the American Association for Cancer Research.

Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

Advertisement