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Research Articles: Therapeutics, Targets, and Development

2-Deoxyglucose induces Akt phosphorylation via a mechanism independent of LKB1/AMP-activated protein kinase signaling activation or glycolysis inhibition

¹ The Winship Cancer Institute and Departments of ² Hematology and Oncology, ³ Human Genetics, and ⁴ Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia and ⁵ Department of Internal Medicine, Tianjin Medical University General Hospital, Tianjian, People's Republic of China

Requests for reprints: Wei Zhou, The Winship Cancer Institute, Emory University School of Medicine, Building C, Room 4084, 1365 Clifton Road Northeast, Atlanta, GA 30322. Phone: 404-778-2134; Fax: 404-778-5530. E-mail: wei.zhou{at}emoryhealthcare.org

Abstract

The compound 2-deoxyglucose (2-DG) enhances chemotherapy/radiotherapy in cell lines and animal models, prompting two phase I clinical trials with this cancer therapeutic. Although its mechanism of action has not been fully elucidated, it is hypothesized that the molecular basis of 2-DG activity is related to glycolysis inhibition. Here, we report that 2-DG induced Akt phosphorylation at Thr³⁰⁸ and Ser⁴⁷³ as early as 15 min post-treatment. These phosphorylation events required phosphatidylinositol-3-kinase activity but were not related to LKB1/AMP-activated protein kinase signaling, the inhibition of glycolysis or epidermal growth factor receptor signaling. The 2-DG-mediated Akt phosphorylation also led to the phosphorylation of Akt downstream targets, such as Foxo3a, GSK3β, and Chk1. Because the functional consequence of Akt activation includes chemotherapy/radiotherapy resistance, our data suggested that the combination of phosphatidylinositol-3-kinase/Akt inhibitory agents in 2-DG-based chemotherapy/radiotherapy may result in enhanced therapeutic efficacy. [Mol Cancer Ther 2008;7(4):809–17]

Grant support: American Cancer Society grant RSG-05-038-01-CCE (W. Zhou), National Cancer Institute grants P01 CA116676-01A1 (F. Khuri) and RO1 CA 118470-01 (S-Y. Sun), and Elsa J. Pardee Foundation (A.I. Marcus). W. Zhou, F. Khuri, A.I. Marcus, and S-Y. Sun are Georgia Cancer Coalition distinguished cancer scholars.

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.

Note: D. Zhong and X. Liu contributed equally to this work.

Received 8/14/07; revised 12/11/07; accepted 2/20/08.