This Article Full Text Full Text (PDF) Supplementary Material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wangpaichitr, M. Articles by Lampidis, T. J. PubMed PubMed Citation Articles by Wangpaichitr, M. Articles by Lampidis, T. J.

Research Articles: Therapeutics, Targets, and Development

Intrinsically lower AKT, mammalian target of rapamycin, and hypoxia-inducible factor activity correlates with increased sensitivity to 2-deoxy-D-glucose under hypoxia in lung cancer cell lines

¹ Department of Molecular Cell Biology and Anatomy, Miller School of Medicine, University of Miami and ² Division of Hematology and Oncology, V.A. Medical Center, Miami, Florida

Requests for reprints: Theodore J. Lampidis, University of Miami School of Medicine, P.O. Box 016960, 1600 Northwest 10th Avenue, Miami, FL 33101. Phone: 305-243-4846; Fax: 305-243-3414. E-mail: tlampidi{at}med.miami.edu

Abstract

Down-regulation by small interfering RNA or absence of hypoxia-inducible factor (HIF-1) has been shown to lead to increased sensitivity to glycolytic inhibitors in hypoxic tumor cells. In surveying a number of tumor types for differences in intrinsic levels of HIF under hypoxia, we find that the reduction of the upstream pathways of HIF, AKT, and mammalian target of rapamycin (mTOR) correlates with increased toxic effects of 2-deoxy-D-glucose (2-DG) in lung cancer cell lines when treated under hypoxia. Because HIF-1 translation is regulated by mTOR, we examined the effects of blocking mTOR under hypoxia with an analogue of rapamycin (CCI-779) in those cell lines that showed increased mTOR and AKT activity and found that HIF-1 down-regulation coincided with increased 2-DG killing. CCI-779, however, was ineffective in increasing 2-DG toxicity in cell lines that did not express HIF. These results support the hypothesis that although mTOR inhibition leads to the blockage of numerous downstream targets, CCI-779 increases the toxicity of 2-DG in hypoxic cells through down-regulation of HIF-1. Overall, our findings show that CCI-779 hypersensitizes hypoxic tumor cells to 2-DG and suggests that the intrinsic expression of AKT, mTOR, and HIF in lung cancer, as well as other tumor types, may be important in dictating the decision on how best to use 2-DG alone or in combination with CCI-799 to kill hypoxic tumor cells clinically. [Mol Cancer Ther 2008;7(6):1506–13]

Grant support: NIH/NCI grant RO1CA037109 and Threshold Pharmaceuticals Award (T.J. Lampidis) and V.A. Research Merit Award (N. Savaraj).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 11/27/07; revised 3/ 3/08; accepted 3/11/08.