[Erratum to "Mechanisms of castration resistance : intratumoral hypoxia stimulates the androgen receptor expression. [Prog. Urol. 26 (3) (2016 159-167]]

International audiencePurposeTumor hypoxia and its biological consequence lead to microenvironment adaptation of tumor initiation, promotion and progression. The aim of the study was to observe the influence of hypoxia on the expression of the androgen receptor (AR), using an original model of multicellular spheroids obtained from castration-resistant prostate tumor cells.MaterialTwo human castration-resistant prostate cancer cell lines have been used to generate multicellular tumor spheroids (MTS). The conditions and duration of incubation modulated the final size of the MTS and the intrinsic hypoxia gradient. The expression of AR was studied by immunohistochemistry (IHC) and secretion of PSA measured in the culture medium.ResultsThe IHC expression of AR was characterized by a decreasing gradient from the periphery to the center of MTS (less intense in central hypoxic zone), corresponding to a nuclear translocation of activated AR. This result was proportionally correlated with the duration of hypoxic incubation period. Hypoxia caused significant increase in AR expression at 6 h of oxygen deprivation. This activation of AR was correlated with transcriptional activity increase of target genes, including increased secretion of PSA.ConclusionThis demonstration of activation, increased expression and increased transcriptional activity of AR by hypoxia is the first to have been made with an original model of hypoxia, closer to reality than previous models, i.e. close to tissue hypoxia observed in primary prostate cancer

Butyric Acid-Induced T-Cell Apoptosis Is Mediated by Caspase-8 and -9 Activation in a Fas-Independent Manner

Our previous study demonstrated that butyric acid, an extracellular metabolite of periodontopathic bacteria, induced apoptosis in murine thymocytes, splenic T cells, and human Jurkat cells. In this study, we examined whether CD95 ligand-receptor interaction is involved in butyric acid-induced T-cell apoptosis. Flow cytometry analysis indicated that expression of Fas in Jurkat and T cells from peripheral blood mononuclear cells was not affected by butyric acid treatment. Furthermore, the expression of Fas and FasL protein in Western blotting was not affected by butyric acid treatment. Coincubation with blocking anti-Fas antibodies prevented Fas-induced apoptosis but not butyric acid-induced apoptosis. Anti-FasL antibodies also did not prevent butyric acid-induced apoptosis at any dose examined. Although cytotoxic anti-Fas antibody affected butyric acid-induced apoptosis, a synergistic effect was not seen. Time-dependent activation of caspase-8 and -9 was recognized in butyric acid- as well as Fas-mediated apoptosis. IETD-CHO and LEHD-CHO, specific inhibitors of caspase-8 and -9, respectively, completely blocked Fas-mediated apoptosis and partially prevented butyric acid-induced apoptosis. These results suggest that the Fas-FasL interaction is not involved in butyric acid-induced apoptosis and that caspase-8 and -9-dependent apoptosis plays an important role in butyric acid-induced apoptosis, as well as Fas-induced apoptosis