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Published April 9, 2013 | Supplemental Material + Published
Journal Article Open

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 a glioblastoma multiforme (GBM) cancer cell model, we examined the response of signaling networks to targeted pathway inhibition between 21% and 1% pO_2. 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% pO_2, 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 pO_2 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.

Additional Information

© 2013 National Academy of Sciences. Contributed by R. D. Levine, February 15, 2013 (sent for review December 17, 2012). Published online before print March 25, 2013. This work was funded by National Cancer Institute Grant 5U54 CA119347 (to J.R.H.), National Institute of Neurological Disorders and Stroke Grant R01 NS73831 (to P.S.M.), the Ben and Catherine Ivy Foundation, the Jean Perkins Foundation, and the Grand Duchy of Luxembourg. F.R. is a Director of Research with Fonds National de Recherche Scientifique, Belgium. Author contributions: W.W., Q.S., and J.R.H. designed research; F.R. developed and applied the theory; R.D.L. developed the theory; W.W., Q.S., L.Q., and D.B.S. performed research; Y.S.S. and R.D.L. contributed new reagents/analytic tools; W.W., F.R., R.D.L., and J.R.H. analyzed data; and W.W., Q.S., P.S.M., R.D.L., and J.R.H. wrote the paper.

Attached Files

Published - PNAS-2013-Wei-E1352-60.pdf

Supplemental Material - sapp.pdf


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August 22, 2023
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