38 research outputs found
Insulin Receptor Isoform A and Insulin-like Growth Factor II as Additional Treatment Targets in Human Osteosarcoma
Abstract
Despite the frequent presence of an insulin-like growth factor I receptor (IGFIR)-mediated autocrine loop in osteosarcoma (OS), interfering with this target was only moderately effective in preclinical studies. Here, we considered other members of the IGF system that might be involved in the molecular pathology of OS. We found that, among 45 patients with OS, IGF-I and IGFBP-3 serum levels were significantly lower, and IGF-II serum levels significantly higher, than healthy controls. Increased IGF-II values were associated with a decreased disease-free survival. After tumor removal, both IGF-I and IGF-II levels returned to normal values. In 23 of 45 patients, we obtained tissue specimens and found that all expressed high mRNA level of IGF-II and >IGF-I. Also, isoform A of the insulin receptor (IR-A) was expressed at high level in addition to IGFIR and IR-A/IGFIR hybrids receptors (HRA). These receptors were also expressed in OS cell lines, and simultaneous impairment of IGFIR, IR, and Hybrid-Rs by monoclonal antibodies, siRNA, or the tyrosine kinase inhibitor BMS-536924, which blocks both IGFIR and IR, was more effective than selective anti-IGFIR strategies. Also, anti–IGF-II-siRNA treatment in low-serum conditions significantly inhibited MG-63 OS cells that have an autocrine circuit for IGF-II. In summary, IGF-II rather than IGF-I is the predominant growth factor produced by OS cells, and three different receptors (IR-A, HRA, and IGFIR) act complementarily for an IGF-II–mediated constitutive autocrine loop, in addition to the previously shown IGFIR/IGF-I circuit. Cotargeting IGFIR and IR-A is more effective than targeting IGF-IR alone in inhibiting OS growth. [Cancer Res 2009;69(6):2443–52
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GREB1 is a novel androgen-regulated gene required for prostate cancer growth
BACKGROUND Gene regulated in breast cancer 1 (GREB1) is a novel estrogen-regulated gene shown to play a pivotal role in hormone-stimulated breast cancer growth. GREB1 is expressed in the prostate and its putative promoter contains potential androgen receptor (AR) response elements. METHODS We investigated the effects of androgens on GREB1 expression and its role in androgen-dependent prostate cancer growth. RESULTS Real-time PCR demonstrated high level GREB1 expression in benign prostatic hypertrophy (BPH), localized prostate cancer (L-PCa), and hormone refractory prostate cancer (HR-PCa). Androgen treatment of AR-positive prostate cancer cells induced dose-dependent GREB1 expression, which was blocked by anti-androgens. AR binding to the GREB1 promoter was confirmed by chromatin immunoprecipitation (ChIP) assays. Suppression of GREB1 by RNA interference blocked androgen-stimulated LNCaP cell proliferation. CONCLUSIONS GREB1 is expressed in proliferating prostatic tissue and prostate cancer, is regulated by androgens, and suppression of GREB1 blocks androgen-induced growth suggesting GREB1 may be critically involved in prostate cancer proliferation. Prostate © 2006 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49275/1/20403_fta.pd
The Identification of CELSR3 and Other Potential Cell Surface Targets in Neuroendocrine Prostate Cancer.
UNLABELLED
Although recent efforts have led to the development of highly effective androgen receptor (AR)-directed therapies for the treatment of advanced prostate cancer, a significant subset of patients will progress with resistant disease including AR-negative tumors that display neuroendocrine features [neuroendocrine prostate cancer (NEPC)]. On the basis of RNA sequencing (RNA-seq) data from a clinical cohort of tissue from benign prostate, locally advanced prostate cancer, metastatic castration-resistant prostate cancer and NEPC, we developed a multi-step bioinformatics pipeline to identify NEPC-specific, overexpressed gene transcripts that encode cell surface proteins. This included the identification of known NEPC surface protein CEACAM5 as well as other potentially targetable proteins (e.g., HMMR and CESLR3). We further showed that cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) knockdown results in reduced NEPC tumor cell proliferation and migration in vitro. We provide in vivo data including laser capture microdissection followed by RNA-seq data supporting a causal role of CELSR3 in the development and/or maintenance of the phenotype associated with NEPC. Finally, we provide initial data that suggests CELSR3 is a target for T-cell redirection therapeutics. Further work is now needed to fully evaluate the utility of targeting CELSR3 with T-cell redirection or other similar therapeutics as a potential new strategy for patients with NEPC.
SIGNIFICANCE
The development of effective treatment for patients with NEPC remains an unmet clinical need. We have identified specific surface proteins, including CELSR3, that may serve as novel biomarkers or therapeutic targets for NEPC
The androgen receptor can signal through Wnt/β-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens
<p>Abstract</p> <p>Background</p> <p>A crucial event in Prostate Cancer progression is the conversion from a hormone-sensitive to a hormone-refractory disease state. Correlating with this transition, androgen receptor (AR) amplification and mutations are often observed in patients failing hormonal ablation therapies. β-Catenin, an essential component of the canonical Wnt signaling pathway, was shown to be a coactivator of the AR signaling in the presence of androgens. However, it is not yet clear what effect the increased levels of the AR could have on the Wnt signaling pathway in these hormone-refractory prostate cells.</p> <p>Results</p> <p>Transient transfections of several human prostate cancer cell lines with the AR and multiple components of the Wnt signaling pathway demonstrate that the AR overexpression can potentiate the transcriptional activities of Wnt/β-Catenin signaling. In addition, the simultaneous activation of the Wnt signaling pathway and overexpression of the AR promote prostate cancer cell growth and transformation at castration levels of androgens. Interestingly, the presence of physiological levels of androgen or other AR agonists inhibits these effects. These observations are consistent with the nuclear co-localization of the AR and β-Catenin shown by immunohistochemistry in human prostate cancer samples. Furthermore, chromatin immunoprecipitation assays showed that Wnt3A can recruit the AR to the promoter regions of Myc and Cyclin D1, which are well-characterized downstream targets of the Wnt signalling pathway. The same assays demonstrated that the AR and β-Catenin can be recruited to the promoter and enhancer regions of a known AR target gene PSA upon Wnt signaling. These results suggest that the AR is promoting Wnt signaling at the chromatin level.</p> <p>Conclusion</p> <p>Our findings suggest that the AR signaling through the Wnt/β-Catenin pathway should be added to the well established functional interactions between both pathways. Moreover, our data show that via this interaction the AR could promote prostate cell malignancy in a ligand-independent manner.</p
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Decreased Egr-1 expression in human, mouse and rat mammary cells and tissues correlates with tumor formation
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