Expression of p NTR has been linked to

Expression of p75NTR has been linked to several aspects of aggressive glioma growth, including migration and invasion, by various mechanisms in a large number of elegant studies [6], [7], [26], [27]. Our study adds to this literature by demonstrating specific roles in hypoxic tumor cells and regulation of the phenotypic cellular 2536 to oxygen shortage. These studies together support the development of therapeutic strategies to target p75NTR and its signaling in glioma, and there are several conceivable strategies that may be employed to this end. Like many other cell surface markers associated with aggressive brain tumor growth like Notch and CD44, p75NTR is a substrate of γ-secreatase and may be sensitive to γ-secretase inhibitors. In our study, we complemented RNAi targeting of p75NTR with the use of the Ro 08–2750 inhibitor of p75NTR – ligand interactions. This inhibitor was effective in diminishing hypoxia-induced stemness dependent on p75NTR in our in vitro setting, and should be evaluated further for in vivo use.
Conclusions Taken together, our findings highlight p75NTR as a regulator of the hypoxic response of glioma cells, and a sustainer of glioma stemness. Targeting p75NTR may offer a new therapeutic strategy against aggressive brain tumors.
Acknowledgements We thank Christina Möller for her skillful technical assistance. We thank Prof. M. Chao for kindly providing the p75NTR antibody and plasmids, and Prof. P. Barker for plasmids. We thank the human glioblastoma cell culture resource (www.hgcc.se) (Lene Uhrbom, Bengt Westermark, Karin Forsberg Nilsson and Sven Nelander, Uppsala University, Sweden) for the primary human GBM samples. This work was supported by grants from the Swedish Research Council (2014-2406), the Ragnar Söderberg Foundation (M20/16), the Swedish Childhood Cancer Foundation (TJ2014-0016, PR2017-0040), the Swedish Cancer Society (2016/328), Ollie & Elof Ericssons foundation, Jeanssons stiftelser, the Gyllenstierna Krapperup's Foundation, Gunnar Nilssons cancerstiftelse, the Segerfalk foundation, the Crafoord foundation, Gösta Miltons donationsfond, the Mary Beve foundation, and Magnus Bergvalls stiftelse.
Introduction Hypoxia inducible factor-1a (HIF-1a) is an important regulator of the cellular and systemic hypoxia response in both normal tissues and cancer cells. HIF-1a is involved in cell survival, apoptosis, cellular metabolic shift and cancer progression through its downstream effectors (Chowdhury et al., 2017; Obacz et al., 2013; Wang et al., 2011). HIF-1a is a key protein involved in the cellular response to hypoxia and its expression in bone marrow is stable and high (Zhang and Sadek, 2014). Low-oxygen microenvironment in the bone marrow is important and helpful to maintain self-renewal and differentiation of hematopoietic stem and progenitor cells (Zhang and Sadek, 2014). Studies found HIF-1a is helpful to maintain hematopoietic stem cells (HSCs)’ quiescence and self-renew. The response of HSC to ROS has been reported to be modulated by HIF-1a (Kocabas et al., 2012). HSCs lack of HIF-1a show elevated levels of ROS with decreased HSC quiescence and increased apoptosis (Kocabas et al., 2012). Moreover, numerous studies have demonstrated that reactive oxygen species (ROS) can modulate HIF stability and activity by affecting the rate of HIF-1a hydroxylation (Movafagh et al., 2015). HIF-1a regulates metabolism from the oxidant stress response to the modulation of glycolysis by stimulating expression of glucose transporters, glycolytic enzymes and glycolytic inducing factors (Zhang and Sadek, 2014). To meet their energy needs, glycolysis is used by HSCs in the bone marrow but not mitochondrial oxidative phosphorylation (Zhang and Sadek, 2014). In previous study, we found significantly increased ROS level and decreased HIF-1a protein level in bone marrow in benzene-exposed mice with hematotoxicity (Meng et al., 2016). Benzene is a well-known environmental and occupational pollutant and class I human carcinogen, widely used in petrochemical solvent and industry (Duarte-Davidson et al., 2001). Chronic benzene exposure can lead to multiple hematological disorders, such as aplastic anemia, myelodysplasia, and leukemia (Snyder, 2012). Although numerous studies on the mechanism of benzene toxicity have been done, including epidemiological study of population, animal experiments and molecular biology research, the exact mechanism of benzene hematotoxicity still need to be elucidated.