Upon detachment from the extracellular matrix, tumor epithelial cells and tumor-associated endothelial cells are capable of overcoming anoikis, gain survival benefits, and hence contribute to the process of metastasis. The focal-adhesion complex formation recruits the association of key adaptor proteins such as FAK (focal-adhesion kinase). Vimentin, paxillin, and talin are responsible for mediating the interaction between the actin cytoskeleton and integrins. Talin is an early-recruited focal-adhesion player that is of structural and functional significance in mediating interactions with integrin cytoplasmic tails leading to destabilization of the transmembrane complex and resulting in rearrangements in the extracellular integrin compartments that mediate integrin activation. Talin-mediated integrin activation plays a definitive role in integrin-mediated signaling and induction of downstream survival pathways leading to protection from anoikis and consequently resulting in cancer progression to metastasis. We recently reported that talin expression is significantly increased in prostate cancer compared with benign and normal prostate tissue and that this overexpression correlates with progression to metastatic disease implicating a prognostic value for talin during tumor progression. At the molecular level, talin is functionally associated with enhanced survival and proliferation pathways and confers anoikis resistance and metastatic spread of primary tumor cells via activation of the Akt survival pathway. In this review, we discuss the growing evidence surrounding the value of talin as a prognostic marker of cancer progression to metastasis and as therapeutic target in advanced prostate cancer, as well as the current understanding of mechanisms regulating its signaling activity in cancer.

Introduction Mechanistic, translational and pharmacological studies led to the identification, preferred localization, binding characteristics, structure and functional properties of α1-adrenoceptor (α1-AR) subtypes in the bladder neck, bladder and prostate gland. The evidence gathered on α1-ARs, provided a molecular platform for the development of subtype selective antagonists, resulting in more effective approaches targeting those receptors for the treatment of outlet bladder obstruction and benign prostate hyperplasia. Areas Covered This review provides a comprehensive synopsis of advances over the last decade, in the design and optimization of Prazosin, Doxazosin, Terazosin quinazoline-based derivatives as clinically effective α1-AR antagonists. Furthermore, it discusses evidence on the metabolic and growth interference action by these agents, in addition to their smooth-muscle relaxing effects. The new action recognition emerges from compelling data on the inhibitory effect of quinazoline-based antagonists on primary tumor growth and progression to metastasis. In addition to the cellular findings in the prostate, functional validation and therapeutic impact of selected lead pharmaceutically optimized derivatives in the context of impairing vascularity and triggering tumor apoptosis, are also summarized. Expert Opinion The expanding knowledge on targeting intracellular signalling pathways driving the cellular response via an α1-AR dependent and independent antagonistic action, must be invested towards the optimization of new agents that while bypassing AR, exhibit improved pharmacological efficacy against human cancer.

Cancer cell resistance to anoikis driven by aberrant signaling sustained by the tumor microenvironment confers high invasive potential and therapeutic resistance. We recently generated a novel lead quinazoline-based Doxazosin® derivative, DZ-50, which impairs tumor growth and metastasis via anoikis. Genome-wide analysis in the human prostate cancer cell line DU-145 identified primary downregulated targets of DZ-50, including genes involved in focal adhesion integrity (fibronectin, integrin-α6 and talin), tight junction formation (claudin-11) as well as insulin growth factor binding protein 3 (IGFBP-3) and the angiogenesis modulator thrombospondin 1 (TSP-1). Confocal microscopy demonstrated structural disruption of both focal adhesions and tight junctions by the downregulation of these gene targets, resulting in decreased cell survival, migration and adhesion to extracellular matrix (ECM) components in two androgen-independent human prostate cancer cell lines, PC-3 and DU-145. Stabilization of cell-ECM interactions by overexpression of talin-1 and/or exposing cells to a fibronectin-rich environment mitigated the effect of DZ-50. Loss of expression of the intracellular focal adhesion signaling effectors talin-1 and integrin linked kinase (ILK) sensitized human prostate cancer to anoikis. Our findings suggest that DZ-50 exerts its antitumor effect by targeting the key functional intercellular interactions, focal adhesions and tight junctions, supporting the therapeutic significance of this agent for the treatment of advanced prostate cancer.

The androgen-signaling pathway with the androgen receptor (AR) as its key molecule is widely understood to influence prostate tumor growth significantly even after androgen ablation. Under androgen-deprived conditions, the AR may be activated inappropriately through interaction with other molecules, including cyclic AMP-dependent protein kinase A (PKA). In a previous study, we have shown that knocking down the AR significantly inhibits prostate tumor growth. In this study, we show that combined inhibition of the AR and the regulatory subunit I alpha of PKA (RIa) with small interference RNAs significantly increased the growth-inhibitory and proapoptotic effects of AR knockdown. This treatment strategy was effective in androgen-sensitive and in androgen ablation-resistant prostate cancer cells. In addition, we report that downregulating PKA RIa was sufficient to inhibit PKA signaling and interestingly also impaired AR expression and activation. Vice versa, AR knockdown induced a decline in PKA RIa, associated with reduced PKA activity. This mutual influence on expression level was specific, because siRNAs against the AR did not affect expression of PKA RIa in AR negative DU-145 cells and a siRNA control did not affect protein expression. Another important finding of our study was that depletion of PKA RIa also potentiated the antiproliferative effect of the antiandrogen bicalutamide in androgen-sensitive LNCaP. We therefore concluded that combined inhibition of PKA RIa and AR may be a promising new therapeutic option for prostate cancer patients and might be superior to solely preventing AR expression.