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Progression of prostate cancer (PC) to terminal castration-resistant PC (CRPC) involves a diverse set of intermediates, and androgen receptor (AR) is the key mediator of PC initiation and progression to CRPC. Hence, identification of factors involved in the regulation of AR expression and function is a necessary first-step to improve disease outcome. In this study, we identified ubiquitous βArrestin 1 (βArr1) as a regulator of AR function in CRPC. Unbiased gene expression analysis of public datasets revealed increased levels of ARRB1 (the gene encoding βArr1) in CRPC when compared to normal tissue. Further, βArr1 expression correlated with enhanced AR transcriptional function in these datasets. The βArr1 partitions to both nucleus and cytosol and mechanistic studies showed that nuclear, and not cytosolic, βArr1 formed a complex with AR and AR-coregulator βCatenin and that the heterotrimeric protein complex was recruited to androgen-response elements of AR-regulated genes. Functionally, we demonstrate that depletion of βArr1 attenuates PC cell and tumor growth and metastasis, and rescued expression of nuclear, but not cytosolic, βArr1 restores the PC colony growth and invasion of Matrigel in vitro and tumor growth and metastasis in mice. The targeting of βArr1-regulated AR transcriptional function may be used in the development of new drugs to treat lethal CRPC.

Androgen receptor (AR) has a pivotal role in the growth and survival of prostate cancer (PCa). Arrestin2 (Arr2) is a ubiquitous scaffolding/adaptor protein first characterized as a regulator of G protein-coupled receptor signaling. In this study, we report that Arr2 additionally functions as a positive regulator of AR expression and function in PCa cells. Expression level of Arr2 correlates with that of AR, and knockdown of Arr2 inhibits the expression of AR and its effectors prostate-specific antigen, transmembrane protease serine 2, FK506-binding protein 51 and fatty acid synthase. Mechanistically, the knockdown of Arr2 attenuates the binding of AR to androgen response elements and consequently decreases transcription of AR-regulated genes. The inhibition of AR by Arr2 knockdown occurs in both androgen-dependent and castration-resistant PCa (CRPC) cells, although the effect is more prominent in CRPC. Arr2 knockdown inhibits the in vitro CRPC cell proliferation, prostasphere growth and invasion, as well as the in vivo prostate tumor formation, local invasion and distant metastasis. These results illustrate a new role for Arr2 in the expression and activation of AR and its potential relevance as a target for therapeutic intervention and monitoring of disease progression. [ABSTRACT FROM AUTHOR]

Chemoresistance to platinums, such as cisplatin, is of critical concern in the treatment of ovarian cancer. Recent evidence has linked epithelial-mesenchymal transition (EMT) as a contributing mechanism. The current study explored the connection between cellular responses to cisplatin and EMT in ovarian cancer. Expression microarrays were utilized to estimate the EMT status as a binary phenotype, and the transcriptional responses of 46 ovarian cancer cell lines to cisplatin were measured at dosages equivalent to 50% growth inhibition. Phenotypic responses to cisplatin were quantified with respect to cell number, proliferation rate and apoptosis, and then compared with the epithelial or mesenchymal status. Ovarian cancer cell lines with an epithelial status exhibited higher resistance to cisplatin treatment in the MTS assay than those with a mesenchymal status. Pathway analyses revealed the induction of G1/S- and S-phase genes (P=0.001) and the activation of multiple NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) downstream genes (P=0.0016) by cisplatin selectively in epithelial-like cell lines. BrdU incorporation and Caspase-3/7 release assays confirmed impaired apoptosis in epithelial-like ovarian cancer cells. In clinical samples, we observed resistance to single platinum treatment and the selective activation of the NF-κB pathway by platinum in ovarian cancers with an epithelial status. Overall, our results suggest that, in epithelial-like ovarian cancer cells, NF-κB activation by cisplatin may lead to defective apoptosis, preferential proliferation arrest and a consequential decreased sensitivity to cisplatin. [ABSTRACT FROM AUTHOR]

Chondrosarcoma is the second most common sarcoma in bone malignancy and is characterized by a high metastatic potential. Angiogenesis is essential for the cancer metastasis. Endothelin-1 (ET-1) has been implicated in tumor angiogenesis and metastasis. However, the relationship of ET-1 with vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma cells is mostly unknown. Here, we found that the expression of ET-1 and VEGF were correlated with tumor stage and were significantly higher than that in the normal cartilage. Exogenous ET-1 with chondrosarcoma cells promoted VEGF expression and subsequently increased migration and tube formation in endothelial progenitor cells. ET-1 increased VEGF expression and angiogenesis through ETAR, integrin-linked kinase (ILK), Akt and hypoxia-inducible factor-1α (HIF-1α) signaling cascades. Knockdown of ET-1 decreased VEGF expression and also abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and Matrigel plug nude mice model in vivo. In addition, in the xenograft tumor angiogenesis model, knockdown of ET-1 significantly reduced tumor growth and tumor-associated angiogenesis. Taken together, these results indicate that ET-1 occurs through ETAR, ILK and Akt, which in turn activates HIF-1α, resulting in the activation of VEGF expression and contributing to the angiogenesis and tumor growth of human chondrosarcoma cells. [ABSTRACT FROM AUTHOR]

β-Arrestins 1 and 2 are multifunctional adaptor proteins originally discovered for their role in desensitizing seven-transmembrane receptor signaling via the heterotrimeric guanine nucleotide-binding proteins. Recently identified roles of β-arrestins include regulation of cancer cell chemotaxis and proliferation. Herein, we report that β-arrestin1 expression regulates breast tumor colonization in nude mice and cancer cell viability during hypoxia. β-Arrestin1 robustly interacts with nuclear hypoxia-induced factor-1α (HIF-1α) that is stabilized during hypoxia and potentiates HIF-1-dependent transcription of the angiogenic factor vascular endothelial growth factor-A (VEGF-A). Increased expression of β-arrestin1 in human breast cancer (infiltrating ductal carcinoma or IDC and metastatic IDC) correlates with increased levels of VEGF-A. While the anti-angiogenic drug thalidomide inhibits HIF-1-dependent VEGF transcription in breast carcinoma cells, it does not prevent HIF-1α stabilization, but leads to aberrant localization of HIF-1α to the perinuclear compartments and surprisingly stimulates nuclear export of β-arrestin1. Additionally, imatinib mesylate that inhibits release of VEGF induces nuclear export of β-arrestin1-HIF-1α complexes. Our findings suggest that β-arrestin1 regulates nuclear signaling during hypoxia to promote survival of breast cancer cells via VEGF signaling and that drugs that induce its translocation from the nucleus to the cytoplasm could be useful in anti-angiogenic and breast cancer therapies. [ABSTRACT FROM AUTHOR]

P73 is important in drug-induced apoptosis in some cancer cells, yet its role in the regulation of chemosensitivity in ovarian cancer (OVCA) is poorly understood. Furthermore, if and how the deregulation of p73-mediated apoptosis confers resistance to cisplatin (CDDP) treatment is unclear. Here we demonstrate that TAp73α over-expression enhanced CDDP-induced PARP cleavage and apoptosis in both chemosensitive (OV2008 and A2780s) and their resistant counterparts (C13* and A2780cp) and another chemoresistant OVCA cells (Hey); in contrast, the effect of ΔNp73α over-expression was variable. P73α downregulation attenuated CDDP-induced PUMA and NOXA upregulation and apoptosis in OV2008 cells. CDDP decreased p73α steady-state protein levels in OV2008, but not in C13*, although the mRNA expression was identical. CDDP-induced p73α downregulation was mediated by a calpain-dependent pathway. CDDP induced calpain activation and enhanced its cytoplasmic interaction and co-localization with p73α in OV2008, but not C13* cells. CDDP increased the intracellular calcium concentration ([Ca2+]i) in OV2008 but not C13* whereas cyclopiazonic acid (CPA), a Ca2+-ATPase inhibitor, caused this response and calpain activation, p73α processing and apoptosis in both cell types. CDDP-induced [Ca2+]i increase in OV2008 cells was not effected by the elimination of extracellular Ca2+, but this was attenuated by the depletion of internal Ca2+ store, indicating that mobilization of intracellular Ca2+] stores was potentially involved. These findings demonstrate that p73α and its regulation by the Ca2+-mediated calpain pathway are involved in CDDP-induced apoptosis in OVCA cells and that dysregulation of Ca2+/calpain/p73 signaling may in part be the pathophysiology of CDDP resistance. Understanding the cellular and molecular mechanisms of chemoresistance will direct the development of effective strategies for the treatment of chemoresistant OVCA. [ABSTRACT FROM AUTHOR]