1. Cancer Biology
Download icon

Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma

  1. Nataša Pavlović
  2. Carlemi Calitz
  3. Kess Thanapirom
  4. Guiseppe Mazza
  5. Krista Rombouts
  6. Pär Gerwins
  7. Femke Heindryckx  Is a corresponding author
  1. Uppsala University, Sweden
  2. University College London, United Kingdom
Research Article
  • Cited 2
  • Views 931
  • Annotations
Cite this article as: eLife 2020;9:e55865 doi: 10.7554/eLife.55865

Abstract

Hepatocellular carcinoma (HCC) is a liver tumor that usually arises in patients with cirrhosis. Hepatic stellate cells are key players in the progression of HCC, as they create a fibrotic micro-environment and produce growth factors and cytokines that enhance tumor cell proliferation and migration. We assessed the role of endoplasmic reticulum (ER) stress in the cross-talk between stellate cells and HCC-cells. Mice with a fibrotic HCC were treated with the IRE1α-inhibitor 4μ8C, which reduced tumor burden and collagen deposition. By co-culturing HCC-cells with stellate cells, we found that HCC-cells activate IREα in stellate cells, thereby contributing to their activation. Inhibiting IRE1α blocked stellate cell activation, which then decreased proliferation and migration of tumor cells in different in vitro 2D and 3D co-cultures. In addition, we also observed cell-line specific direct effects of inhibiting IRE1α in tumor cells.

Article and author information

Author details

  1. Nataša Pavlović

    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  2. Carlemi Calitz

    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  3. Kess Thanapirom

    University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Guiseppe Mazza

    University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Krista Rombouts

    University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Pär Gerwins

    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  7. Femke Heindryckx

    Medical Cell Biology, Uppsala University, Uppsala, Sweden
    For correspondence
    femke.heindryckx@mcb.uu.se
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1987-7676

Funding

Cancerfonden (CAN 2017/518)

  • Femke Heindryckx

Svenska Sällskapet för Medicinsk Forskning (S17-0092)

  • Femke Heindryckx

OE och Edla Johanssons stiftelse

  • Femke Heindryckx

Olga Jonssons stiftelse

  • Femke Heindryckx

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 by FELASA. All of the animals were handled according to approved institutional animal care and Uppsala University approved protocols were used. The protocol was approved by the Committee on the Ethics of Animal Experiments of Uppsala (C95/14). All effort was made to minimise suffering and to decrease animal usage.

Reviewing Editor

  1. Lynne-Marie Postovit, University of Alberta, Canada

Publication history

  1. Received: February 9, 2020
  2. Accepted: October 26, 2020
  3. Accepted Manuscript published: October 26, 2020 (version 1)
  4. Version of Record published: November 12, 2020 (version 2)

Copyright

© 2020, Pavlović 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

  • 931
    Page views
  • 146
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cancer Biology
    2. Cell Biology
    Margaret E Torrence et al.
    Research Article Updated

    The mechanistic target of rapamycin complex 1 (mTORC1) stimulates a coordinated anabolic program in response to growth-promoting signals. Paradoxically, recent studies indicate that mTORC1 can activate the transcription factor ATF4 through mechanisms distinct from its canonical induction by the integrated stress response (ISR). However, its broader roles as a downstream target of mTORC1 are unknown. Therefore, we directly compared ATF4-dependent transcriptional changes induced upon insulin-stimulated mTORC1 signaling to those activated by the ISR. In multiple mouse embryo fibroblast and human cancer cell lines, the mTORC1-ATF4 pathway stimulated expression of only a subset of the ATF4 target genes induced by the ISR, including genes involved in amino acid uptake, synthesis, and tRNA charging. We demonstrate that ATF4 is a metabolic effector of mTORC1 involved in both its established role in promoting protein synthesis and in a previously unappreciated function for mTORC1 in stimulating cellular cystine uptake and glutathione synthesis.

    1. Cancer Biology
    2. Evolutionary Biology
    Juan M Vazquez, Vincent J Lynch
    Research Article Updated

    The risk of developing cancer is correlated with body size and lifespan within species. Between species, however, there is no correlation between cancer and either body size or lifespan, indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Elephants and their relatives (Proboscideans) are a particularly interesting lineage for the exploration of mechanisms underlying the evolution of augmented cancer resistance because they evolved large bodies recently within a clade of smaller-bodied species (Afrotherians). Here, we explore the contribution of gene duplication to body size and cancer risk in Afrotherians. Unexpectedly, we found that tumor suppressor duplication was pervasive in Afrotherian genomes, rather than restricted to Proboscideans. Proboscideans, however, have duplicates in unique pathways that may underlie some aspects of their remarkable anti-cancer cell biology. These data suggest that duplication of tumor suppressor genes facilitated the evolution of increased body size by compensating for decreasing intrinsic cancer risk.