Rho-associated kinase (ROCK) function is essential for cell cycle progression, senescence and tumorigenesis

  1. Sandra Kümper  Is a corresponding author
  2. Faraz K Mardakheh
  3. Afshan McCarthy
  4. Maggie Yeo
  5. Gordon W Stamp
  6. Angela Paul
  7. Jonathan Worboys
  8. Amine Sadok
  9. Claus Jørgensen
  10. Sabrina Guichard
  11. Christopher J Marshall
  1. Institute of Cancer Research, United Kingdom
  2. Cancer Research UK London Research Institute, United Kingdom
  3. Cancer Research UK Manchester Institute, United Kingdom

Abstract

Rho-associated kinases 1 and 2 (ROCK1/2) are Rho-GTPase effectors that control key aspects of the actin cytoskeleton, but their role in proliferation and cancer initiation or progression is not known. Here we provide evidence that ROCK1 and ROCK2 act redundantly to maintain actomyosin contractility and cell proliferation and that their loss leads to cell-cycle arrest and cellular senescence. This phenotype arises from down-regulation of the essential cell-cycle proteins CyclinA, CKS1 and CDK1. Accordingly, while loss of either Rock1 or Rock2 had no negative impact on tumorigenesis in mouse models of non-small cell lung cancer and melanoma, loss of both blocked tumor formation, as no tumors arise in which both Rock1 and Rock2 have been genetically deleted. Our results reveal an indispensable role for ROCK, yet redundant role for isoforms 1 and 2, in cell cycle progression and tumorigenesis, possibly through the maintenance of cellular contractility.

Article and author information

Author details

  1. Sandra Kümper

    Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom
    For correspondence
    sandra.kuemper@icr.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  2. Faraz K Mardakheh

    Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Afshan McCarthy

    Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Maggie Yeo

    Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Gordon W Stamp

    Experimental Pathology Laboratory, Cancer Research UK London Research Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Angela Paul

    Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Jonathan Worboys

    Cancer Research UK Manchester Institute, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Amine Sadok

    Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Claus Jørgensen

    Cancer Research UK Manchester Institute, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Sabrina Guichard

    Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Christopher J Marshall

    Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All animal procedures were approved by the Animal Ethics Committee of the Institute of Cancer Research in accordance with National Home Office regulations under the Animals (Scientific Procedures) Act 1986. The date of approval of the current project license under which this work was carried out was the 07/09/13.

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 8,121
    views
  • 1,718
    downloads
  • 129
    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)

  1. Sandra Kümper
  2. Faraz K Mardakheh
  3. Afshan McCarthy
  4. Maggie Yeo
  5. Gordon W Stamp
  6. Angela Paul
  7. Jonathan Worboys
  8. Amine Sadok
  9. Claus Jørgensen
  10. Sabrina Guichard
  11. Christopher J Marshall
(2016)
Rho-associated kinase (ROCK) function is essential for cell cycle progression, senescence and tumorigenesis
eLife 5:e12203.
https://doi.org/10.7554/eLife.12203

Share this article

https://doi.org/10.7554/eLife.12203

Further reading

    1. Cancer Biology
    Pierluigi Scerbo, Benjamin Tisserand ... Bertrand Ducos
    Research Article

    Why does a normal cell possibly harboring genetic mutations in oncogene or tumor suppressor genes becomes malignant and develops a tumor is a subject of intense debate. Various theories have been proposed but their experimental test has been hampered by the unpredictable and improbable malignant transformation of single cells. Here, using an optogenetic approach we permanently turn on an oncogene (KRASG12V) in a single cell of a zebrafish brain that, only in synergy with the transient co-activation of a reprogramming factor (VENTX/NANOG/OCT4), undergoes a deterministic malignant transition and robustly and reproducibly develops within 6 days into a full-blown tumor. The controlled way in which a single cell can thus be manipulated to give rise to cancer lends support to the ‘ground state theory of cancer initiation’ through ‘short-range dispersal’ of the first malignant cells preceding tumor growth.

    1. Cancer Biology
    Han V Han, Richard Efem ... Richard Z Lin
    Research Article

    Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca−/− KPC (named αKO) cancer cells induces clonal enrichment of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression, and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally enriched CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally enriched T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.