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PMID: 17030613 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Molecular and cellular biology ·Vol. 26 ·No. 24 ·2006-12-00 ·Pages 9517-32

Blais JD, Addison CL, Edge R, Falls T, Zhao H, Wary K, Koumenis C, Harding HP, Ron D, Holcik M, Bell JC

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(-/-) 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.

MeSH Terms
Animals Cell Line, Transformed Fibroblasts/enzymology Gene Expression Profiling HT29 Cells Humans Hypoxia/enzymology,genetics,physiopathology Mice Mice, Nude Neoplasms, Experimental/enzymology,genetics,physiopathology Neovascularization, Pathologic/enzymology,genetics,physiopathology Oligonucleotide Array Sequence Analysis Protein Biosynthesis Stress, Physiological/enzymology,genetics,physiopathology eIF-2 Kinase/deficiency,genetics,physiology
Chemicals
PERK kinase eIF-2 Kinase
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Blais Jaime D
Ottawa Health Research Institute, Ottawa, ON K1H 1C4, Canada.
Addison Christina L
Edge Robert
Falls Theresa
Zhao Huijun
Wary Kishore
Koumenis Costas
Harding Heather P
Ron David
Holcik Martin
Bell John C
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.01145-06
Published
2006-12-00
Epub
2006-00-09
Pages
9517-32
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1698539
Subset
IM
Grants
NIDDK NIH HHS · R01 DK047119 · United States
NIEHS NIH HHS · R01 ES008681 · United States
NIEHS NIH HHS · ES08681 · United States
NIDDK NIH HHS · R37 DK047119 · United States
NHLBI NIH HHS · HL079356 · United States
NHLBI NIH HHS · R01 HL079356 · United States
NIDDK NIH HHS · DK47119 · United States
External Links
PubMed source DOI: 10.1128/MCB.01145-06 PMC Full Text View journal details
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