Rac1, a Rho GTPase, modulates diverse cellular processes and is hyperactive in some cancers. Estrogen receptor-alpha (ER) in concert with intracellular signaling pathways regulates genes associated with cell proliferation, tumor development and breast cancer cell survival. Therefore, we examined the possibility of Rac1 and ER crosstalk in breast cancer cells. We found that Rac1 enhanced ER transcriptional activity in breast cancer cells. Vav3, a Rho guanine nucleotide exchange factor that activates Rac1, was an upstream mediator and P21/Cdc42/Rac1 activating kinase-1 (Pak-1) was a downstream effector of Rac1 enhancement of ER activity. These results suggest that Rac1 may prove to be a therapeutic target. To test this hypothesis, we used a small molecule Rac inhibitor, EHT 1864, and found that EHT 1864 inhibited ER transcriptional activity. Furthermore, EHT 1864 inhibited estrogen-induced cell proliferation in breast cancer cells and decreased tamoxifen resistant breast cancer cell growth. EHT 1864 decreased activity of the promoter of the ER gene resulting in downregulation of ER mRNA and protein levels. Therefore, ER downregulation by EHT 1864 is the likely mechanism of EHT 1864-mediated inhibition of ER activity and estrogen-stimulated breast cancer cell proliferation. Since ER plays a critical role in the pathogenesis of breast cancer and the Rac inhibitor EHT 1864 downregulates ER expression and breast cancer cell proliferation, further investigation of the therapeutic potential of Rac1 targeting in the treatment of breast cancer is warranted.

Advanced hormone-sensitive prostate cancer responds to androgen-deprivation therapy (ADT); however, therapeutic options for recurrent castration-resistant disease are limited. Because growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) are regulated in an autocrine fashion in prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists-MIA-602, MIA-606, and MIA-690-on the growth of androgen-dependent as well as castration-resistant prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human prostate cancer cell lines. Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared with castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro, MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of MIA-602. In vivo, MIA-602 was more effective than MIA-606 and MIA-690 and decreased 22Rv1 xenograft tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in body weight occurred. In vitro, the VCaP cell line was minimally inhibited by MIA-602, but in vivo, this line showed a substantial reduction in growth of xenografts in response to MIA-602, indicating both direct and systemic inhibitory effects. MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist MIA-602 for treatment of both androgen-dependent and CRPC.androgen-independent | G protein-coupled receptor | hypothalamic neurohormone | neuropeptide | targeted therapy

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BackgroundChlamydia trachomatis is the most common sexually transmitted bacterial infection globally. Currently, there are no vaccines available despite the efforts made to develop a protective one. Polymorphic membrane protein D (PmpD) is an attractive immunogen candidate as it is conserved among strains and it is target of neutralizing antibodies. However, its high molecular weight and its complex structure make it difficult to handle by recombinant DNA techniques. Our aim is to predict B-cell and T-cell epitopes of PmpD.MethodA sequence (Genbank AAK69391.2) having 99–100% identity with various serovars of C. trachomatis was used for predictions. NetMHC and NetMHCII were used for T-cell epitope linked to MHC I or MHC II alleles prediction, respectively. BepiPred predicted linear B-cell epitopes. For three dimensional epitopes, PmpD was homology-modeled by Raptor X. Surface epitopes were predicted on its globular structure using DiscoTope.ResultsNetMHC predicted 271 T-cell epitopes of 9-12aa with weak affinity, and 70 with strong affinity to MHC I molecules. NetMHCII predicted 2903 T-cell epitopes of 15aa with weak affinity, and 742 with strong affinity to MHC II molecules. Twenty four linear B-cell epitopes were predicted. Raptor X was able to model 91% of the three-dimensional structure whereas 57 residues of discontinuous epitopes were suggested by DiscoTope. Six regions containing B-cell and T-cell epitopes were identified by at least two predictors.ConclusionsPmpD has potential B-cell and T-cell epitopes distributed throughout the sequence. Thus, several fragments were identified as valuable candidates for subunit vaccines against C. trachomatis.

We have determined the percentage of ab and gd T cells by flow cytometry as well as serum interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R) levels by enzyme-linked immunosorbent assay in kidney allograft recipients with acute, chronic or stable graft evolution. The percentage of CD4 and CD8 T cells in transplanted patients was lower than in the control group (P < 0.001) with the exception of CD8 gd T cells from patients with stable evolution (P > 0.05). The serum levels of IL-6 and sIL-6R in acute and chronic rejection were higher than in the controls (P < 0.05). No differences in IL-6 levels were observed between the stable evolution and the control groups (P > 0.05). The levels of sIL-6R were higher in stable evolution patients than in the controls (P < 0.05) and no differences were observed between the chronic and stable evolution patients (P > 0.05). IL-6 decreased in patients with a favourable evolution, increased in those with an increased renal dysfunction and was maintained when the renal dysfunction was not modified. These results suggest that gd T cells could participate in renal allograft maintenance and that IL-6 but not sIL-6R serum levels may provide a prognostic marker for measuring the evolution of kidney allograft.

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