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Subject Review

"Translating" Tumor Hypoxia: Unfolded Protein Response (UPR)–Dependent and UPR-Independent Pathways

¹ Departments of Radiation Oncology, Cancer Biology, and Neurosurgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina and ² Department of Radiation Oncology, Maastricht Radiation Oncology (Maastro) Laboratory, GROW Research Institute, University of Maastricht, Maastricht, the Netherlands

Requests for reprints: Bradly G. Wouters, Department of Radiation Oncology, Maastricht Radiation Oncology (Maastro) Laboratory, GROW Research Institute, USN50/23 University of Maastricht, P.O. Box 616, 6200MD Maastricht, the Netherlands. Phone: 31-43-3882912; Fax: 31-43-3884540. E-mail: brad.wouters{at}maastro.unimaas.nl or Contantinos Koumenis, Department of Radiation Oncology, NRC, Room 411, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157. Phone: 336-713-7637; Fax: 336-713-7639. E-mail: ckoumen{at}wfubmc.edu

Abstract

Poor oxygenation (hypoxia) is present in the majority of human tumors and is associated with poor prognosis due to the protection it affords to radiotherapy and chemotherapy. Hypoxia also elicits multiple cellular response pathways that alter gene expression and affect tumor progression, including two recently identified separate pathways that strongly suppress the rates of mRNA translation during hypoxia. The first pathway is activated extremely rapidly and is mediated by phosphorylation and inhibition of the eukaryotic initiation factor 2. Phosphorylation of this factor occurs as part of a coordinated endoplasmic reticulum stress response program known as the unfolded protein response and activation of this program is required for hypoxic cell survival and tumor growth. Translation during hypoxia is also inhibited through the inactivation of a second eukaryotic initiation complex, eukaryotic initiation factor 4F. At least part of this inhibition is mediated through a Redd1 and tuberous sclerosis complex 1/2–dependent inhibition of the mammalian target of rapamycin kinase. Inhibition of mRNA translation is hypothesized to affect the cellular tolerance to hypoxia in part by promoting energy homeostasis. However, regulation of translation also results in a specific increase in the synthesis of a subset of hypoxia-induced proteins. Consequently, both arms of translational control during hypoxia influence gene expression and phenotype. These hypoxic response pathways show differential activation requirements that are dependent on the level of oxygenation and duration of hypoxia and are themselves highly dynamic. Thus, the severity and duration of hypoxia can lead to different biological and therapeutic consequences. (Mol Cancer Res 2006;4(7):423–36)

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