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Research Articles: Therapeutics, Targets, and Development

Mitochondrial regulation by c-Myc and hypoxia-inducible factor-1 controls sensitivity to econazole

¹ Arthritis and Immune Disorder Research Centre, University Health Network and ² Department of Immunology, University of Toronto, Toronto, Ontario, Canada and ³ Department of Hematology, Tongji Hospital, Tongji Medical College, and Huazhong University of Science and Technology, Wuhan, China

Requests for reprints: Stuart A. Berger, Arthritis and Immune Disorder Research Centre, University Health Network, Toronto Medical Discovery Tower, 8th Floor, Room 8-354, 101 College Street, Toronto, Ontario, Canada M5G 1L7. Phone: 416-581-7457; Fax: 416-581-7457. E-mail: berger{at}uhnres.utoronto.ca

Abstract

Econazole is an azole antifungal with anticancer activity that blocks Ca²⁺ influx and stimulates endoplasmic reticulum (ER) Ca²⁺ release through the generation of mitochondrial reactive oxygen species (ROS), resulting in sustained depletion of ER Ca²⁺ stores, protein synthesis inhibition, and cell death. c-Myc, a commonly activated oncogene, also promotes apoptosis in response to growth factor withdrawal and a variety of chemotherapeutic agents. We have investigated the role of c-myc in regulating sensitivity to econazole. Here, we show that c-myc-negative cells are profoundly resistant to econazole. c-Myc-negative rat fibroblasts failed to generate mitochondrial ROS in response to econazole and consequently failed to deplete the ER of Ca²⁺. HL60 cells knocked down for c-myc expression also displayed decreased ROS generation and decreased econazole sensitivity. Addition of H₂O₂ restored sensitivity to econazole in both c-myc-negative rat fibroblasts and c-myc knocked-down HL60 cells, supporting a role for ROS in cell death induction. c-Myc-negative cells and HL60 cells knocked down for c-myc have reduced mitochondrial content compared with c-myc-positive cells. The hypoxia sensor, hypoxia-inducible factor-1 (HIF-1), interacts antagonistically with c-myc and also regulates mitochondrial biogenesis. Knockdown of HIF-1 in c-myc-negative cells increased mitochondrial content restored ROS generation in response to econazole and increased sensitivity to the drug. Taken together, these results show that c-myc and HIF-1 regulate sensitivity to econazole by modulating the ability of the drug to generate mitochondrial ROS. [Mol Cancer Ther 2008;7(3):483–91]

Grant support: National Cancer Institute of Canada (S.A. Berger).

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.

Received 9/ 7/07; revised 11/ 6/07; accepted 12/ 6/07.