SUMMARY A handful of tumor-derived cell lines form the mainstay of cancer therapeutic development, yielding drugs with impact typically measured as months to disease progression. To develop more effective breast cancer therapeutics and more readily understand their clinical impact, we constructed a functional metabolic portrait of 46 independently-derived breast cell lines. Our analysis of glutamine uptake and dependence identified a subset of triple negative samples that are glutamine auxotrophs. Ambient glutamine indirectly supports environmental cystine acquisition via the xCT antiporter, which is expressed on 1/3 of triple negative tumors in vivo. xCT inhibition with the clinically approved anti-inflammatory Sulfasalazine decreases tumor growth revealing a therapeutic target in breast tumors of poorest prognosis, and a lead compound for rapid, effective drug development.
Reactive oxygen species (ROS) are implicated in the pathophysiology of various diseases, including cancer. In this study, we show that JunD, a member of the AP-1 family of transcription factors, reduces tumor angiogenesis by limiting Ras-mediated production of ROS. Using junD-deficient cells, we demonstrate that JunD regulates genes involved in antioxidant defense, H2O2 production, and angiogenesis. The accumulation of H2O2 in junD-/- cells decreases the availability of FeII and reduces the activity of HIF prolyl hydroxylases (PHDs) that target hypoxia-inducible factors-alpha (HIFalpha) for degradation. Subsequently, HIF-alpha proteins accumulate and enhance the transcription of VEGF-A, a potent proangiogenic factor. Our study uncovers the mechanism by which JunD protects cells from oxidative stress and exerts an antiangiogenic effect. Furthermore, we provide new insights into the regulation of PHD activity, allowing immediate reactive adaptation to changes in O2 or iron levels in the cell.
Identifying new targeted therapies that kill tumor cells while sparing normal tissue is a major challenge of cancer research. Using a high-throughput chemical synthetic lethal screen, we sought to identify compounds that exploit the loss of the von Hippel–Lindau (VHL) tumor suppressor gene, which occurs in about 80% of renal cell carcinomas (RCCs). RCCs, like many other cancers, are dependent on aerobic glycolysis for ATP production, a phenomenon known as the Warburg effect. The dependence of RCCs on glycolysis is in part a result of induction of glucose transporter 1 (GLUT1). Here, we report the identification of a class of compounds, the 3-series, exemplified by STF-31, which selectively kills RCCs by specifically targeting glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. Treatment with these agents inhibits the growth of RCCs by binding GLUT1 directly and impeding glucose uptake in vivo without toxicity to normal tissue. Activity of STF-31 in these experimental renal tumors can be monitored by [18F]fluorodeoxyglucose uptake by micro–positron emission tomography imaging, and therefore, these agents may be readily tested clinically in human tumors. Our results show that the Warburg effect confers distinct characteristics on tumor cells that can be selectively targeted for therapy.
The hypoxia-inducible transcription factors (HIFs) directly and indirectly mediate cellular adaptation to reduced oxygen tensions. Recent studies have shown that the histone demethylase genes JMJD1A, JMJD2B, and JARID1B are HIF targets, suggesting that HIFs indirectly influence gene expression at the level of histone methylation under hypoxia. In this study, we identify a subset of hypoxia-inducible genes that are dependent on JMJD1A in both renal cell and colon carcinoma cell lines. JMJD1A regulates the expression of adrenomedullin (ADM) and growth and differentiation factor 15 (GDF15) under hypoxia by decreasing promoter histone methylation. In addition, we demonstrate that loss of JMJD1A is sufficient to reduce tumor growth in vivo, demonstrating that histone demethylation plays a significant role in modulating growth within the tumor microenvironment. Thus, hypoxic regulation of JMJD1A acts as a signal amplifier to facilitate hypoxic gene expression, ultimately enhancing tumor growth.Cellular hypoxia occurs when the demands of growth and metabolism of a tissue surpass the vascular oxygen supply. In response to hypoxia, cells undergo specific alterations in gene expression patterns geared to promote cell survival and maintain homeostasis. This response not only is important in normal development but also is a critical part in the progression of cancers (7). Hypoxia has been implicated in activating the metabolic shift to anaerobic glycolysis, promoting the epithelial-to-mesenchymal transition (EMT), inducing the secretion of proangiogenic factors, and remodeling the extracellular matrix. Although several transcription programs are activated in response to hypoxia, the hypoxia-inducible factors (HIFs) regulate a critical repertoire of genes, making them central regulators of the cellular response to hypoxia (10, 34).The HIFs are heterodimeric transcription factors consisting of an oxygen-sensitive alpha subunit (HIF-1␣, HIF-2␣, or HIF-3␣) and a constitutively expressed HIF-1 subunit (also known as the arylhydrocarbon nuclear translocator [ARNT]). Under conditions where oxygen concentration is not limiting, HIF-␣ subunits are hydroxylated by prolyl-hydroxylases, targeting them for ubiquitin-mediated degradation by the von Hippel-Lindau tumor suppressor (VHL) (18,19). Under hypoxic conditions, HIF-␣ protein is stabilized, translocates to the nucleus, dimerizes with ARNT, and binds hypoxia-responsive elements (HREs) in the regulatory regions of target genes (51). HIF-1␣ and HIF-2␣ will bind the same sequences in cells but do not have completely overlapping abilities to regulate genes (5, 17, 44). Under certain conditions, HIF-3␣ functions as a dominant negative, antagonizing the activity of HIF-1 and HIF-2 (32).Several hundred genes are induced in response to hypoxia, and a great deal of research has been focused on identifying direct HIF target genes (34). The massive transcriptional reorganization mediated by hypoxia and HIFs suggests that changes in histone modification would create epigenetic reinforcement o...
Prolyl hydroxylation of hypoxible-inducible factor alpha (HIF-␣
SUMMARY Sustained angiogenesis, through either local sprouting (angiogenesis) or the recruitment of bone marrow-derived cells (BMDCs) (vasculogenesis), is essential to the development of a tumor. How BMDCs are recruited to the tumor and their contribution to the tumor vasculature is poorly understood. Here we demonstrate that both IL-8 and Angiogenin contribute to the complementary pathways of angiogenesis and BMDC mobilization to increase tumor growth. These two factors are regulated by PHD2 in a HIF-independent but NF-κB-dependent manner. PHD2 levels are decreased in human cancers compared to corresponding normal tissue and correlate with an increase in mature blood vessels. Thus, PHD2 plays a critical role in regulating tumor angiogenesis.
Hypoxia poses many problems to the treatment of cancer. Hypoxic tumors are more resistant to chemotherapy and radiation. In addition, hypoxia induces a number of genes responsible for increased invasion, aggressiveness, and metastasis of tumors. The augmented metastatic potential due to hypoxia-mediated gene expression is discussed in this section. Particular attention is given to recent studies of specific genes involved in the key steps of metastasis, including extracellular matrix interactions, migration, and proliferation.
Renal Cell Carcinomas (RCCs) are refractory to standard therapies. The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in 75% of RCCs. By screening for small molecules selectively targeting VHL-deficient RCC cells, we identified STF-62247. STF-62247 induces cytotoxicity and reduces tumor growth of VHL-deficient RCC cells compared to genetically matched cells with wild-type VHL. STF-62247-stimulated toxicity occurs in a HIF-independent manner through autophagy. Reduction of protein levels of essential autophagy pathway components reduces sensitivity of VHL-deficient cells to STF-62247. Using the yeast deletion pool, we show that loss of proteins involved in Golgi trafficking increased killing by STF-62247. Thus, we found a small molecule that selectively induces cell death in VHL-deficient cells that represents a paradigm shift for targeted therapy.
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