Cited by 50Cancer Cells and MetastasisCellular Mechanics and InteractionsMechanisms of cancer metastasis

Dysregulation of Ezrin Phosphorylation Prevents Metastasis and Alters Cellular Metabolism in Osteosarcoma

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Ren, Ling, Hong, Sung-Hyeok, Chen, Qing-Rong, Briggs, Joseph, Cassavaugh, Jessica, Srinivasan, Satish, Lizardo, Michael M., Mendoza, Arnulfo +4 more·2012·Cancer Research

Published version of a preprint

Abstract

Ezrin links the plasma membrane to the actin cytoskeleton where it plays a pivotal role in the metastatic progression of several human cancers; however, the precise mechanistic basis for its role remains unknown. Here, we define transitions between active (phosphorylated open) and inactive (dephosphorylated closed) forms of Ezrin that occur during metastatic progression in osteosarcoma. In our evaluation of these conformations we expressed C-terminal mutant forms of Ezrin that are open (phosphomimetic T567D) or closed (phosphodeficient T567A) and compared their biologic characteristics to full-length wild-type Ezrin in osteosarcoma cells. Unexpectedly, cells expressing open, active Ezrin could form neither primary orthotopic tumors nor lung metastases. In contrast, cells expressing closed, inactive Ezrin were also deficient in metastasis but were unaffected in their capacity for primary tumor growth. By imaging single metastatic cells in the lung, we found that cells expressing either open or closed Ezrin displayed increased levels of apoptosis early after their arrival in the lung. Gene expression analysis suggested dysregulation of genes that are functionally linked to carbohydrate and amino acid metabolism. In particular, cells expressing closed, inactive Ezrin exhibited reduced lactate production and basal or ATP-dependent oxygen consumption. Collectively, our results suggest that dynamic regulation of Ezrin phosphorylation at amino acid T567 that controls structural transitions of this protein plays a pivotal role in tumor progression and metastasis, possibly in part by altering cellular metabolism. Cancer Res; 72(4); 1001–12. ©2011 AACR.

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  • The cytoskeletal linker ezrin provides a scaffold for PI3K-AKT signalling and facilitates survival through stresses that disseminated tumour cells first encounter within the lung.

    “The cytoskeletal linker ezrin provides a scaffold for PI3K-AKT signalling and facilitates survival through the stresses that disseminated tumour cells first encounter within the lung 72,73,74 .”

    From Osteosarcoma (2022) · cites this paper as [74]

  • Ex vivo techniques have been adapted to study tumour-host interactions, screen for metastasis-related vulnerabilities, and validate hits from other screens.

    “These techniques have been adapted to study tumour-host interactions, to screen for metastasis-related vulnerabilities and to validate hits identified in other screens 74,75,92,216,217,218,219 .”

    From Osteosarcoma (2022) · cites this paper as [74]

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Authors
Ren, L., Hong, S.-H., Chen, Q.-R., Briggs, J., Cassavaugh, J., Srinivasan, S., Lizardo, M. M., Mendoza, A., Xia, A. Y., Avadhani, N., Khan, J., & Khanna, C.
Affiliations
  • National Institute of Allergy and Infectious Diseases (US)
  • Authors' Affiliations: 1Tumor and Metastasis Biology Section, 2Oncogenomics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute; 3Office of Biomedical Informatics, Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; and 4Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
Corresponding author
Khanna, Chand
Venue
Cancer Research
Published
2012-02-14
Volume
72
Issue
4
Pages
1001-1012
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
OpenAlex
W1974284378
Cited by
50
References
45
Citations by year
2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 6 · 2019: 3 · 2017: 5 · 2016: 7 · 2015: 3 · 2014: 6 · 2013: 6 · 2012: 2
FWCI
2.20
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (R01CA022762, R01 CA-22762)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Keywords
ezrin, phosphorylation, osteosarcoma, metastasis, actin cytoskeleton, plasma membrane, cellular metabolism, lactic acid production, oxygen consumption, apoptosis, lung metastasis, carbohydrate metabolism, amino acid metabolism
MeSH terms
Ezrin, Animals, Cytoskeletal Proteins, Humans, Lung Neoplasms, Mutation, Phenotype, Phosphorylation, Protein Conformation, Osteosarcoma, Gene Expression, Microscopy, Video, Cell Line, Tumor, Mice

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