Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Castration resistant prostate cancer (CRPC) develops as a consequence of hormone therapies used to deplete androgens in advanced prostate cancer patients. CRPC cells are able to grow in a low androgen environment and this is associated with anomalous activity of their endogenous androgen receptor (AR) despite the low systemic androgen levels in the patients. Therefore, the reactivated tumor cell androgen signaling pathway is thought to provide a target for control of CRPC. Previously, we reported that Hedgehog (Hh) signaling was conditionally activated by androgen deprivation in androgen sensitive prostate cancer cells and here we studied the potential for cross-talk between Hh and androgen signaling activities in androgen deprived and androgen independent (AI) prostate cancer cells.</p> <p>Results</p> <p>Treatment of a variety of androgen-deprived or AI prostate cancer cells with the Hh inhibitor, cyclopamine, resulted in dose-dependent modulation of the expression of genes that are regulated by androgen. The effect of cyclopamine on endogenous androgen-regulated gene expression in androgen deprived and AI prostate cancer cells was consistent with the suppressive effects of cyclopamine on the expression of a reporter gene (luciferase) from two different androgen-dependent promoters. Similarly, reduction of smoothened (Smo) expression with siRNA co-suppressed expression of androgen-inducible KLK2 and KLK3 in androgen deprived cells without affecting the expression of androgen receptor (AR) mRNA or protein. Cyclopamine also prevented the outgrowth of AI cells from androgen growth-dependent parental LNCaP cells and suppressed the growth of an overt AI-LNCaP variant whereas supplemental androgen (R1881) restored growth to the AI cells in the presence of cyclopamine. Conversely, overexpression of Gli1 or Gli2 in LNCaP cells enhanced AR-specific gene expression in the absence of androgen. Overexpressed Gli1/Gli2 also enabled parental LNCaP cells to grow in androgen depleted medium. AR protein co-immunoprecipitates with Gli2 protein from transfected 293T cell lysates.</p> <p>Conclusions</p> <p>Collectively, our results indicate that Hh/Gli signaling supports androgen signaling and AI growth in prostate cancer cells in a low androgen environment. The finding that Gli2 co-immunoprecipitates with AR protein suggests that an interaction between these proteins might be the basis for Hedgehog/Gli support of androgen signaling under this condition.</p

AMI radio continuum observations of young stellar objects with known outflows

We present 16 GHz (1.9 cm) deep radio continuum observations made with the Arcminute Microkelvin Imager (AMI) of a sample of low-mass young stars driving jets. We combine these new data with archival information from an extensive literature search to examine spectral energy distributions (SEDs) for each source and calculate both the radio and sub-mm spectral indices in two different scenarios: (1) fixing the dust temperature (Td) according to evolutionary class; and (2) allowing Td to vary. We use the results of this analysis to place constraints on the physical mechanisms responsible for the radio emission. From AMI data alone, as well as from model fitting to the full SED in both scenarios, we find that 80 per cent of the objects in this sample have spectral indices consistent with freefree emission. We find an average spectral index in both Td scenarios, consistent with freefree emission. We examine correlations of the radio luminosity with bolometric luminosity, envelope mass and outflow force, and find that these data are consistent with the strong correlation with envelope mass seen in lower luminosity samples. We examine the errors associated with determining the radio luminosity and find that the dominant source of error is the uncertainty on the opacity index, beta. We examine the SEDs for variability in these young objects, and find evidence for possible radio flare events in the histories of L1551 IRS 5 and Serpens SMM 1