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Hypoxia induces a phase transition within a kinase signaling network in cancer cells.

Hypoxia is a near-universal feature of cancer, promoting glycolysis, cellular proliferation, and angiogenesis. The molecular mechanisms of hypoxic signaling have been intensively studied, but the impact of changes in oxygen partial pressure (pO2) on the state of signaling networks is less clear. In... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America April 9, 2013, Vol.110(15), pp.E1352-E1360
Main Author: Wei, Wei
Other Authors: Shi, Qihui , Remacle, Francoise , Qin, Lidong , Shackelford, David B , Shin, Young Shik , Mischel, Paul S , Levine, R D , Heath, James R
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1303060110
Link: http://search.proquest.com/docview/1326143547/?pq-origsite=primo
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recordid: proquest1326143547
title: Hypoxia induces a phase transition within a kinase signaling network in cancer cells.
format: Article
creator:
  • Wei, Wei
  • Shi, Qihui
  • Remacle, Francoise
  • Qin, Lidong
  • Shackelford, David B
  • Shin, Young Shik
  • Mischel, Paul S
  • Levine, R D
  • Heath, James R
subjects:
  • Animals–Metabolism
  • Brain Neoplasms–Pathology
  • Cell Hypoxia–Metabolism
  • Cell Line, Tumor–Genetics
  • Gene Expression Regulation, Neoplastic–Metabolism
  • Glioblastoma–Metabolism
  • Humans–Methods
  • Mice–Metabolism
  • Monte Carlo Method–Metabolism
  • Neoplasm Transplantation–Metabolism
  • Neoplasms–Metabolism
  • Oxygen–Metabolism
  • Proteomics–Metabolism
  • Signal Transduction–Metabolism
  • Tor Serine-Threonine Kinases–Metabolism
  • Mtor Protein, Human
  • Tor Serine-Threonine Kinases
  • Oxygen
ispartof: Proceedings of the National Academy of Sciences of the United States of America, April 9, 2013, Vol.110(15), pp.E1352-E1360
description: Hypoxia is a near-universal feature of cancer, promoting glycolysis, cellular proliferation, and angiogenesis. The molecular mechanisms of hypoxic signaling have been intensively studied, but the impact of changes in oxygen partial pressure (pO2) on the state of signaling networks is less clear. In a glioblastoma multiforme (GBM) cancer cell model, we examined the response of signaling networks to targeted pathway inhibition between 21% and 1% pO2. We used a microchip technology that facilitates quantification of a panel of functional proteins from statistical numbers of single cells. We find that near 1.5% pO2, the signaling network associated with mammalian target of rapamycin (mTOR) complex 1 (mTORC1)--a critical component of hypoxic signaling and a compelling cancer drug target--is deregulated in a manner such that it will be unresponsive to mTOR kinase inhibitors near 1.5% pO2, but will respond at higher or lower pO2 values. These predictions were validated through experiments on bulk GBM cell line cultures and on neurosphere cultures of a human-origin GBM xenograft tumor. We attempt to understand this behavior through the use of a quantitative version of Le Chatelier's principle, as well as through a steady-state kinetic model of protein interactions, both of which indicate that hypoxia can influence mTORC1 signaling as a switch. The Le Chatelier approach also indicates that this switch may be thought of as a type of phase transition. Our analysis indicates that certain biologically complex cell behaviors may be understood using fundamental, thermodynamics-motivated principles.
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1303060110
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleHypoxia induces a phase transition within a kinase signaling network in cancer cells.
creatorWei, Wei ; Shi, Qihui ; Remacle, Francoise ; Qin, Lidong ; Shackelford, David B ; Shin, Young Shik ; Mischel, Paul S ; Levine, R D ; Heath, James R
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identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1303060110
subjectAnimals–Metabolism ; Brain Neoplasms–Pathology ; Cell Hypoxia–Metabolism ; Cell Line, Tumor–Genetics ; Gene Expression Regulation, Neoplastic–Metabolism ; Glioblastoma–Metabolism ; Humans–Methods ; Mice–Metabolism ; Monte Carlo Method–Metabolism ; Neoplasm Transplantation–Metabolism ; Neoplasms–Metabolism ; Oxygen–Metabolism ; Proteomics–Metabolism ; Signal Transduction–Metabolism ; Tor Serine-Threonine Kinases–Metabolism ; Mtor Protein, Human ; Tor Serine-Threonine Kinases ; Oxygen
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descriptionHypoxia is a near-universal feature of cancer, promoting glycolysis, cellular proliferation, and angiogenesis. The molecular mechanisms of hypoxic signaling have been intensively studied, but the impact of changes in oxygen partial pressure (pO2) on the state of signaling networks is less clear. In a glioblastoma multiforme (GBM) cancer cell model, we examined the response of signaling networks to targeted pathway inhibition between 21% and 1% pO2. We used a microchip technology that facilitates quantification of a panel of functional proteins from statistical numbers of single cells. We find that near 1.5% pO2, the signaling network associated with mammalian target of rapamycin (mTOR) complex 1 (mTORC1)--a critical component of hypoxic signaling and a compelling cancer drug target--is deregulated in a manner such that it will be unresponsive to mTOR kinase inhibitors near 1.5% pO2, but will respond at higher or lower pO2 values. These predictions were validated through experiments on bulk GBM cell line cultures and on neurosphere cultures of a human-origin GBM xenograft tumor. We attempt to understand this behavior through the use of a quantitative version of Le Chatelier's principle, as well as through a steady-state kinetic model of protein interactions, both of which indicate that hypoxia can influence mTORC1 signaling as a switch. The Le Chatelier approach also indicates that this switch may be thought of as a type of phase transition. Our analysis indicates that certain biologically complex cell behaviors may be understood using fundamental, thermodynamics-motivated principles.
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