Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

MiR-1253 Potentiates Cisplatin Response in Pediatric Group 3 Medulloblastoma by Regulating Ferroptosis

Ranjana K. Kanchan, Naveenkumar Perumal, Parvez Khan, David Doss, Ramakanth Chirravuri Venkata, Ishwor Thapa, Raghupathy Vengoji, Jyoti B. Kaushal, Jawed A. Siddiqui, Mohd Wasim Nasser, Surinder K. Batra, View ORCID ProfileSidharth Mahapatra
doi: https://doi.org/10.1101/2022.01.24.477587
Ranjana K. Kanchan
1Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE 68198, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Naveenkumar Perumal
1Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE 68198, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Parvez Khan
1Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE 68198, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David Doss
1Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE 68198, U.S.A
2School of Medicine, Creighton University, Omaha, NE 68178, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ramakanth Chirravuri Venkata
1Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE 68198, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ishwor Thapa
3School of Interdisciplinary Informatics, University of Nebraska at Omaha, Omaha, NE 68182, U.S.A.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Raghupathy Vengoji
1Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE 68198, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jyoti B. Kaushal
1Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE 68198, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jawed A. Siddiqui
1Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE 68198, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mohd Wasim Nasser
1Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE 68198, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Surinder K. Batra
1Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE 68198, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sidharth Mahapatra
1Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE 68198, U.S.A
4Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE 68198, U.S.A.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Sidharth Mahapatra
  • For correspondence: sidharth.mahapatra@unmc.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Medulloblastoma (MB), the most common malignant pediatric brain tumor and a leading cause of childhood mortality, is stratified into four primary subgroups, WNT (wingless), SHH (sonic hedgehog), group 3, and group 4. Patients with group 3 tumors have the poorest prognosis. Loss of 17p13.3, which houses the tumor suppressor gene miR-1253, is a frequent high-risk feature of group 3 tumors.. In this study, we show that miR-1253 levels can disrupt iron homeostasis, induce oxidative stress and lipid peroxidation, triggering an iron-mediated form of cell death called ferroptosis. In silico and in vitro analyses of group 3 tumors revealed deregulation of ABCB7, a mitochondrial iron transporter and target of miR-1253, and GPX4, a critical regulator of ferroptosis. Restoration of miR-1253 levels in group 3 cell lines resulted in downregulation of ABCB7 and GPX4, consequently increasing cytosolic and mitochondrial labile iron pools, reducing glutathione levels, in turn, resulting in mitochondrial oxidative stress and lipid peroxidation. Together, these events accelerated cancer cell death. Treating miR-1253-expressing cancer cells with cisplatin potentiated cell death by further elevating oxidative stress, depleting glutathione levels, and augmenting lipid peroxidation, with added inhibitory effects on cell viability and colony formation. Treatment with a ferroptosis inhibitor (ferrostatin-1) lead to recovery from the cytotoxic effects of this combination therapy. Together, these findings reveal a novel role for miR-1253 in enhancing ferroptosis to attenuate group 3 tumor cell growth. Our studies provide a proof-of-concept for using miR-based therapeutics to augment current chemotherapeutics in high-risk tumors. Leveraging the tumor-suppressive properties of miRNAs as adjuncts to chemotherapy may provide a promising alternative to current therapeutic strategies.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Funding Information: This work was supported by the National Institutes of Health (NICHD K12HD047349); the Edna Ittner Pediatric Research Support Fund; and the Team Jack Brain Tumor Foundation.

  • Conflicts of Interest: Authors declare that they have no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted January 25, 2022.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
MiR-1253 Potentiates Cisplatin Response in Pediatric Group 3 Medulloblastoma by Regulating Ferroptosis
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
MiR-1253 Potentiates Cisplatin Response in Pediatric Group 3 Medulloblastoma by Regulating Ferroptosis
Ranjana K. Kanchan, Naveenkumar Perumal, Parvez Khan, David Doss, Ramakanth Chirravuri Venkata, Ishwor Thapa, Raghupathy Vengoji, Jyoti B. Kaushal, Jawed A. Siddiqui, Mohd Wasim Nasser, Surinder K. Batra, Sidharth Mahapatra
bioRxiv 2022.01.24.477587; doi: https://doi.org/10.1101/2022.01.24.477587
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
MiR-1253 Potentiates Cisplatin Response in Pediatric Group 3 Medulloblastoma by Regulating Ferroptosis
Ranjana K. Kanchan, Naveenkumar Perumal, Parvez Khan, David Doss, Ramakanth Chirravuri Venkata, Ishwor Thapa, Raghupathy Vengoji, Jyoti B. Kaushal, Jawed A. Siddiqui, Mohd Wasim Nasser, Surinder K. Batra, Sidharth Mahapatra
bioRxiv 2022.01.24.477587; doi: https://doi.org/10.1101/2022.01.24.477587

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cancer Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3571)
  • Biochemistry (7514)
  • Bioengineering (5473)
  • Bioinformatics (20664)
  • Biophysics (10250)
  • Cancer Biology (7925)
  • Cell Biology (11563)
  • Clinical Trials (138)
  • Developmental Biology (6558)
  • Ecology (10129)
  • Epidemiology (2065)
  • Evolutionary Biology (13526)
  • Genetics (9493)
  • Genomics (12784)
  • Immunology (7869)
  • Microbiology (19429)
  • Molecular Biology (7609)
  • Neuroscience (41854)
  • Paleontology (306)
  • Pathology (1252)
  • Pharmacology and Toxicology (2178)
  • Physiology (3247)
  • Plant Biology (6993)
  • Scientific Communication and Education (1290)
  • Synthetic Biology (1941)
  • Systems Biology (5404)
  • Zoology (1107)