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Molecular and Cellular Biology, December 2006, p. 9517-9532, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.01145-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Perk-Dependent Translational Regulation Promotes Tumor Cell Adaptation and Angiogenesis in Response to Hypoxic Stress{triangledown} ,{dagger}

Jaime D. Blais,1,2 Christina L. Addison,1 Robert Edge,1,2 Theresa Falls,1 Huijun Zhao,1 Kishore Wary,4 Costas Koumenis,5 Heather P. Harding,6 David Ron,6 Martin Holcik,3 and John C. Bell1*

Ottawa Health Research Institute, 501 Smyth Rd., Ottawa, Ontario K1H 8L6, Canada,1 Department of Biochemistry, University of Ottawa, Ottawa, Ontario, Canada,2 Apoptosis Research Centre, Children's Hospital of Eastern Ontario, 401 Smyth Rd., Ottawa, Ontario K1H 8L1, Canada,3 Department of Pharmacology, University of Illinois at Chicago, 835 S. Wolcott, Room E403, Chicago, Illinois 60612,4 Department of Radiation Oncology, University of Pennsylvania School of Medicine, 185 John Morgan Building, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104-6072,5 Skirball Institute, New York University School of Medicine, New York, New York 100166

Received 26 June 2006/ Returned for modification 10 August 2006/ Accepted 20 September 2006

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–/– mouse embryonic fibroblasts (MEFs) are smaller and exhibit less angiogenesis than 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 and hypoxic Perk+/+ and Perk–/– MEFs. This analysis revealed that a subset of proangiogenic transcripts is preferentially translated in a Perk-dependent manner; these transcripts include VCIP, an adhesion molecule that promotes cellular adhesion, integrin binding, and capillary morphogenesis. Taken with the concomitant Perk-dependent translational induction of additional proangiogenic 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 antitumor modalities.

* Corresponding author. Mailing address: Ottawa Health Research Institute, 503 Smyth Rd., 3rd floor ORCC, Ottawa, ON K1H 1C4, Canada. Phone: (613) 737-7700, ext. 70439. Fax: (613) 247-3524. E-mail: jbell{at}ohri.ca.

{triangledown} Published ahead of print on 9 October 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2006, p. 9517-9532, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.01145-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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