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Molecular and Cellular Biology, July 2006, p. 5336-5347, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.00166-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

5'-AMP-Activated Protein Kinase (AMPK) Is Induced by Low-Oxygen and Glucose Deprivation Conditions Found in Solid-Tumor Microenvironments

Keith R. Laderoute,1* Khalid Amin,1 Joy M. Calaoagan,1 Merrill Knapp,1 Theresamai Le,1 Juan Orduna,1 Marc Foretz,2 and Benoit Viollet2

Biosciences Division, SRI International, Menlo Park, California 94025,1 INSERM U567, CNRS UMR8104, Department of Endocrinology, Metabolism and Cancer, Institut Cochin, Université Paris 5, 75014 Paris, France2

Received 29 January 2006/ Returned for modification 27 March 2006/ Accepted 26 April 2006

Low oxygen gradients (hypoxia and anoxia) are important determinants of pathological conditions under which the tissue blood supply is deficient or defective, such as in solid tumors. We have been investigating the relationship between the activation of hypoxia-inducible factor 1 (HIF-1), the primary transcriptional regulator of the mammalian response to hypoxia, and 5'-AMP-activated protein kinase (AMPK), another regulatory system important for controlling cellular energy metabolism. In the present study, we used mouse embryo fibroblasts nullizygous for HIF-1{alpha} or AMPK expression to show that AMPK is rapidly activated in vitro by both physiological and pathophysiological low-oxygen conditions, independently of HIF-1 activity. These findings imply that HIF-1 and AMPK are components of a concerted cellular response to maintain energy homeostasis in low-oxygen or ischemic-tissue microenvironments. Finally, we used transformed derivatives of wild-type and HIF-1{alpha}- or AMPK{alpha}-null mouse embryo fibroblasts to determine whether AMPK is activated in vivo. We obtained evidence that AMPK is activated in authentic hypoxic tumor microenvironments and that this activity overlaps with regions of hypoxia detected by a chemical probe. We also showed that AMPK is important for the growth of this tumor model.

* Corresponding author. Mailing address: SRI International, Bldg. L, Rm. A258, 333 Ravenswood Ave., Menlo Park, CA 94025. Phone: (650) 859-3080. Fax: (650) 859-5816. E-mail: keith.laderoute{at}sri.com.

Molecular and Cellular Biology, July 2006, p. 5336-5347, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.00166-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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