A solid tumour forms an organ-like structure that is comprised of cancer cells as well as stroma cells (fibroblasts, inflammatory cells) that are embedded in an extracellular matrix and are nourished by vascular network. However, tumoral microenvironment is heterogeneous due to the abnormal vasculature network and high proliferation rate of cancer cells. Because of these features, some regions are starved from oxygen, a phenomenon called hypoxia. Transient hypoxia is associated with inadequate blood flow while chronic hypoxia is the consequence of the increased oxygen diffusion distance due to tumour expansion. Both types of hypoxia are correlated with poor outcome for patients. Moreover, hypoxia also enhances chemoresistance of cancer cells. Firstly, the delivery of drugs in hypoxic area and cellular uptake of it are affected by hypoxia or associated acidity. Secondly, some chemotherapeutic drugs require oxygen to generate free radicals that contribute to cytotoxicity. Last, hypoxia induces cellular adaptations that compromise the effectiveness of chemotherapy. In response to nutrient deprivation due to hypoxia, the rate of proliferation of cancer cells decreases but chemotherapeutic drugs are more effective against proliferating cells. On the other hand, hypoxia induces adaptation by post-translational and transcriptional changes that promote cell survival and resistance to chemotherapy. Through these changes, hypoxia promotes angiogenesis, shift to glycolytic metabolism, expression of ABC transporters, cell survival by inducing the expression of genes encoding growth factors and the modulation of apoptotic process. The aim of this review is to provide a description of known hypoxia-induced mechanisms of chemoresistance at a cellular level.

As a result of oxygen deprivation (hypoxia), cells undergo different transcriptional adaptations that are in majority dependent on one key transcription factor, hypoxia-inducible factor-1 (HIF-1)

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Background: It is more and more recognized that hypoxia plays a role in the resistance of cancer cells to chemotherapy. However, the mechanisms underlying this resistance still need deeper understanding. The aim of this study was to investigate the effect of hypoxia on this process since hypoxia is one of the hallmarks of tumor environment.

Tumor hypoxia is one of the features of tumor microenvironment that contributes to chemoresistance in particular by cellular adaptations that modulate the apoptotic process. However, the mechanisms involved in this resistance still need deeper understanding. In this study, we investigated the involvement of four transcription factors, c-Myc, nuclear factor kappaB (NF-kappaB), p53, and c-jun/activator protein 1 (AP-1) in the hypoxia-induced resistance to etoposide in HepG2 cells. Whereas the profile of c-Myc and NF-kappaB activity did not fit the effect of hypoxia on caspase 3 activity, hypoxia decreased basal p53 abundance and DNA binding activity as well as p53 etoposide-induced activation. Short interfering RNA (siRNA) silencing evidenced that p53 was required for etoposide-induced apoptosis under normoxia. An inhibition of its activity under hypoxia could thus be responsible at least in part for the protection observed under hypoxic conditions. Moreover, p53 was found to induce the expression of Bak1. We showed that Bak1 was involved in the etoposide-induced apoptosis because Bak1 siRNA decreased it. Conversely, hypoxia increased c-jun DNA binding activity in the presence of etoposide. siRNA-mediated silencing of c-jun increased the responsiveness of cells to etoposide under hypoxia, as shown by an increase in caspase 3 activity and lactate dehydrogenase release. These effects occurred in a p53-independent manner. These data evidenced that hypoxia decreased the responsiveness of HepG2 cells to etoposide at least by two independent pathways involving p53 inhibition and c-jun activation.

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Viruses have coevolved with their host to ensure efficient replication and transmission without inducing excessive pathogenicity that would indirectly impair their persistence. This is exemplified by the bovine leukemia virus (BLV) system in which lymphoproliferative disorders develop in ruminants after latency periods of several years. In principle, the equilibrium reached between the virus and its host could be disrupted by emergence of more pathogenic strains. Intriguingly but fortunately, such a hyperpathogenic BLV strain was never observed in the field or designed in vitro. In this study, we sought to understand the role of envelope N-linked glycosylation with the hypothesis that this posttranslational modification could either favor BLV infection by allowing viral entry or allow immune escape by using glycans as a shield. Using reverse genetics of an infectious molecular provirus, we identified a N-linked envelope glycosylation site (N230) that limits viral replication and pathogenicity. Indeed, mutation N230E unexpectedly leads to enhanced fusogenicity and protein stability. There is no satisfactory treatment for HAM/TSP, and the prognosis for ATLL is still poor despite improved therapies (2). BLV is responsible for major economic losses in cattle due to export limitations, carcass condemnations, and reduction in milk production. BLV infection also correlates with a significant morbidity resulting from opportunistic infections and a decrease in longevity due to tumor development (3). In a proportion (i.e., about one third) of infected cattle, BLV induces a lymphoproliferative disease called persistent lymphocytosis. After a latency period of several years, BLV infection also leads to leukemia and/or lymphoma in a minority (5%) of the infected animals. However, the majority of BLV carriers remain clinically healthy and acts as asymptomatic carriers for viral spread (4). Besides its natural hosts (i.e., cattle, zebu, and water buffalo), BLV can be experimentally transmitted to sheep and goats, where leukemia/lymphoma develops after shorter latency periods (5-7).Retroviral envelope glycoproteins play an important role in the viral life cycle: they contain the recognition site required for entry and mediate cell fusion (8). The BLV envelope is composed of two glycoproteins: a surface (SU) protein, Gp51, and a transmembrane (TM) protein, Gp30, derived from the proteolytic cleavage of a common precursor (gpr72) encoded by the env gene (9-11). The SU protein is N-glycosylated in the rough endoplasmic reticulum by covalent attachment of oligosaccharide chains (12). Although the role of BLV SU-linked glycans is currently unknown, it is expected that N-glycosylation is required for protein folding, stability, or solubility (13). Furthermore, N-glycans are also likely involved in transport of BLV envelope proteins to the cell membrane, binding to cellular receptors and cell-to-cell fusion (14-18) similarly to glycans of the human immunodeficiency virus (HIV) envelope glycoprotein that modulate fusogenicity ...

With 5-year survival rates below 5%, small cell lung carcinoma (SCLC) has very poor prognosis and requires improved therapies. Despite an excellent overall response to first-line therapy, relapses are frequent and further treatments are disappointing. The goal of the study was to improve second-line therapy of SCLC.The effect of chemotherapeutic agents was evaluated in cell lines (apoptosis, reactive oxygen species, and RNA and protein expression) and in mouse models (tumour development).We demonstrate here that valproic acid, a histone deacetylase inhibitor, improves the efficacy of a second-line regimen (vindesine, doxorubicin and cyclophosphamide) in SCLC cells and in mouse models.Transcriptomic profiling integrating microRNA and mRNA data identifies key signalling pathways in the response of SCLC cells to valproic acid, opening new prospects for improved therapies.