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Mol. Cell. Biol. doi:10.1128/MCB.01145-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Perk-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress

Jaime D. Blais, Christina L. Addison, Robert Edge, Theresa Falls, Huijun Zhao, Kishore Wary, Costas Koumenis, Heather P Harding, David Ron, Martin Holcik, and John C. Bell*

Ottawa Health Research Institute, 501 Smyth Rd., Ottawa, Ontario K1H 8L6; Department of Biochemistry, University of Ottawa; Apoptosis Research Centre, Children's Hospital of Eastern Ontario, 401 Smyth Rd., Ottawa, Ontario K1H 8L1, Canada; Department of Pharmacology, University of Illinois at Chicago, 835 S. Wolcott, Room E403, Chicago, IL 60612; Department of Radiation Oncology, University of Pennsylvania School of Medicine, 185 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6072; Skirball Institute, New York University School of Medicine, New York, NY 10016

* To whom correspondence should be addressed. Email: jbell{at}ohri.ca.


  Abstract

It has been well established that the tumor microenvironment can promote tumor cell adaptation and survival. However, the mechanisms that influence malignant progression have not been clearly elucidated. We have previously demonstrated that cells cultured under hypoxic/anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR). Here we show that tumors derived from k-ras transformed Perk-/- MEFs are smaller and exhibit less angiogenesis compared to tumors with an intact ISR. Furthermore, Perk promotes a tumor microenvironment that favors the formation of functional microvessels. These observations were corroborated by a microarray analysis of polysome-bound RNA in aerobic (0h) and hypoxic (4h) Perk+/+ and Perk-/- MEFs. This analysis revealed that a subset of pro-angiogenic transcripts are preferentially translated, in a Perk-dependent manner, including VCIP, an adhesion molecule that promotes cellular adhesion, integrin binding, and capillary morphogenesis. Taken with the concomitant Perk-dependent translational induction of additional pro-angiogenic genes identified by our microarray analysis, this study suggests that Perk plays a role in tumor cell adaptation to hypoxic stress by regulating the translation of angiogenic factors necessary for the development of functional microvessels and further supports the contention that the Perk pathway could be an attractive target for novel anti-tumor modalities.




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