XBP1 is essential for survival under hypoxic conditions and is required for tumor growth

Abstract

Abstract Hypoxia within solid tumors is a major determinant of outcome afteranticancer therapy. Analysis of gene expression changes during hypoxiaindicated that unfolded protein response genes were one of the mostrobustly induced groups of genes. In this study, we investigated thehypoxic regulation of X-box binding protein (XBP1), a major transcrip-tional regulator of the unfolded protein response. Hypoxia induced XBP1at the transcriptional level and activated splicing of its mRNA, resulting inincreased levels of activated XBP1 protein. After exposure to hypoxia,apoptosis increased and clonogenic survival decreased in XBP1-deficientcells. Loss of XBP1 severely inhibited tumor growth due to a reducedcapacity for these transplanted tumor cells to survive in a hypoxic micro-environment. Taken together, these studies directly implicate XBP1 as anessential survival factor for hypoxic stress and tumor growth. IntroductionHypoxia is a physiologically important endoplasmic reticulum (ER)stress common to all solid tumors. Numerous clinical studies havedemonstrated that tumor hypoxia predicts for decreased local control,increased distant metastases, and decreased overall survival in avariety of human tumors (1). Hypoxia selects for tumors with anincreased malignant phenotype (2) and increases the metastatic po-tential of tumor cells (3). Understanding the role of hypoxia intumorigenesis and its influence on anticancer therapy is crucial toimproving current cancer treatments (4).The ER is an extensive intracellular membrane network that ex-tends throughout the cytoplasm and functions primarily to processnewly synthesized secretory and transmembrane proteins. Accumula-tion of unfolded proteins in this compartment causes ER stress andprolonged ER stress ultimately results in cell death. The cellularresponse to ER stress consists of at least two coordinated pathways:(1) rapid translational arrest mediated by pancreatic ER kinase orPKR-like ER kinase (PERK); and (2) transcriptional activation ofunfolded protein response target genes (5, 6). In addition to cancer (7),the unfolded protein response has therapeutic implications in diseasessuch as diabetes, atherosclerosis, viral infection, conformational dis-eases, and cerebrovascular disease (8).Koumenis et al. (9) previously demonstrated that translationalcontrol of protein synthesis during hypoxia occurs through the acti-vation of PERK. These investigators showed that PERK