MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect
- Icahn School of Medicine at Mount Sinai, United States
- Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, United States
- Sanford Burnham Prebys Medical Discovery Institute, United States
- New York University Abu Dhabi, United Arab Emirates
Abstract
Rapid cellular proliferation in early development and cancer depends on glucose metabolism to fuel macromolecule biosynthesis. Metabolic enzymes are presumed regulators of this glycolysis-driven metabolic program, known as the Warburg effect, however few have been identified. We uncover a previously unappreciated role for Mannose phosphate isomerase (MPI) as a metabolic enzyme required to maintain Warburg metabolism in zebrafish embryos and in both primary and malignant mammalian cells. The functional consequences of MPI loss are striking: glycolysis is blocked and cells die. These phenotypes are caused by induction of p53 and accumulation of the glycolytic intermediate Fructose 6-Phosphate, leading to engagement of the hexosamine biosynthetic pathway (HBP), increased O-GlcNAcylation, and p53 stabilization. Inhibiting the HBP through genetic and chemical methods reverses p53 stabilization and rescues the Mpi-deficient phenotype. This work provides mechanistic evidence by which MPI loss induces p53, and identifies MPI as a novel regulator of p53 and Warburg metabolism.
Data availability
-
Transcriptome profiles of surgically resected HCC tumor tissuesPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE10186).
Article and author information
Author details
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K08 DK101340)
- Jaime Chu
The Mindich Child Health and Development Institute at Mount Sinai
- Jaime Chu
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080789)
- Kirsten C Sadler
National Institute on Alcohol Abuse and Alcoholism (R01AA018886)
- Kirsten C Sadler
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK99551)
- Hudson H Freeze
The Rocket Fund
- Hudson H Freeze
National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007792)
- Charles DeRossi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#IACUC-2015-0050) of the Icahn School of Medicine at Mount Sinai.
Copyright
© 2017, DeRossi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,941
- views
-
- 558
- downloads
-
- 28
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect
eLife 6:e22477.
https://doi.org/10.7554/eLife.22477
Further reading
-
- Cancer Biology
- Computational and Systems Biology
This study investigates the variability among patients with non-small cell lung cancer (NSCLC) in their responses to immune checkpoint inhibitors (ICIs). Recognizing that patients with advanced-stage NSCLC rarely qualify for surgical interventions, it becomes crucial to identify biomarkers that influence responses to ICI therapy. We conducted an analysis of single-cell transcriptomes from 33 lung cancer biopsy samples, with a particular focus on 14 core samples taken before the initiation of palliative ICI treatment. Our objective was to link tumor and immune cell profiles with patient responses to ICI. We discovered that ICI non-responders exhibited a higher presence of CD4+ regulatory T cells, resident memory T cells, and TH17 cells. This contrasts with the diverse activated CD8+ T cells found in responders. Furthermore, tumor cells in non-responders frequently showed heightened transcriptional activity in the NF-kB and STAT3 pathways, suggesting a potential inherent resistance to ICI therapy. Through the integration of immune cell profiles and tumor molecular signatures, we achieved an discriminative power (area under the curve [AUC]) exceeding 95% in identifying patient responses to ICI treatment. These results underscore the crucial importance of the interplay between tumor and immune microenvironment, including within metastatic sites, in affecting the effectiveness of ICIs in NSCLC.
-
- Cancer Biology
- Genetics and Genomics
A new approach helps examine the proportion of cancerous and healthy stem cells in patients with chronic myeloid leukemia and how this influences treatment outcomes.
