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Proline-rich tyrosine kinase 2 (Pyk2) expression in prostate epithelium inversely correlated with degree of malignancy of prostate cancers, thus the role of Pyk2 in the regulation of prostate cells proliferation and differentiation was investigate in PC3 cells. Pyk2 can be activated by canonic stimuli such as tumor necrosis factoralpha and lysophosphatidic acid (LPA) in PC3 cells, in addition, LPA stimulated Pyk2 phosphorylation also induced extracellular signal-regulated kinase 1 and 2 activation in these cells. Proliferation of PC3 cell clones (PC3-PKM) expressing a dominant negative kinase-defective Pyk2 mutant is consistently decreased in respect to that of wild type PC3 cells. In addition, PC3-PKM clones underwent total block cell proliferation upon treatment with dibutyryl cAMP. Finally, in the presence of sustained levels of intracellular cAMP, PC3-PKM cells, but not wild type PC3 cells, acquired a neuron-like morphology. Taken together our results suggest that Pyk2 plays a role in the regulation of prostate cell proliferation and, more interestingly, its expression may represents a sensitive marker of prostate state of differentiation.

Resveratrol, a dietary polyphenol, is under consideration as chemopreventive and chemotherapeutic agent for several diseases, including cancer. However, its mechanisms of action and its effects on non-tumor cells, fundamental to understand its real efficacy as chemopreventive agent, remain largely unknown. Proline-rich tyrosine kinase 2 (PYK2), a non-receptor tyrosine kinase acting as signaling mediator of different stimuli, behaves as tumor-suppressor in prostate. Since, PYK2 and RSV share several fields of interaction, including oxidative stress, we have investigated their functional relationship in human non-transformed prostate EPN cells and in their tumor-prone counterpart EPN-PKM, expressing a PYK2 dead-kinase mutant. We show that RSV has a strong biological activity in both cell lines, decreasing ROS production, inducing morphological changes and reversible growth arrest, and activating autophagy but not apoptosis. Interestingly, the PYK2 mutant increases basal ROS and autophagy levels, and modulates the intensity of RSV effects. In particular, the anti-oxidant effect of RSV is more potent in EPN than in EPN-PKM, whereas its anti-proliferative and pro-autophagic effects are more significant in EPN-PKM. Consistently, PYK2 depletion by RNAi replicates the effects of the PKM mutant. Taken together, our results reveal that PYK2 and RSV act on common cellular pathways and suggest that RSV effects on prostate cells may depend on mutational-state or expression levels of PYK2 that emerges as a possible mediator of RSV mechanisms of action. Moreover, the observation that resveratrol effects are reversible and not associated to apoptosis in tumor-prone EPN-PKM cells suggests caution for its use in humans. [ABSTRACT FROM AUTHOR]

Although prostate carcinoma is an aggressive cancer preferentially metastasizing to the bones, many prostate tumors remain localized and confined to the prostate indefinitely. Prediction of the behavior of anatomically localized and moderately differentiated prostate tumors remains difficult because of lack of prognostic markers. Cell motility is an important step in the progression of epithelial tumor toward invasive metastatic carcinomas and changes in the expression and function of adhesion molecules contribute to the acquisition of a more malignant phenotype. Proline-rich tyrosine kinase 2 (Pyk2) is implicated in regulating the organization of actin cytoskeleton, a process critical for cell migration, mitosis, and tumor metastasis. In this report, we investigated whether Pyk2 played a role in the acquisition of an aggressive phenotype in prostate cell. Data reported here demonstrate that loss of Pyk2 kinase function results in induction of cell motility and migration in EPN cells, a line of non-transformed epithelial cells derived from human normal prostate tissue. Changes in motility and migration of prostate cells were associated with changes in the expression of several proteins involved in cell adhesion and reorganization of actin cytoskeleton. Ablation of Pyk2 kinase activity caused a dramatic decrease of the expression of E-cadherin and IRS1 and an increase of the expression of α5-integrin. In addition, a massive reorganization of actin cytoskeleton was observed. Our data indicate that Pyk2 plays a central role in the mechanism that regulate cell–cell and cell–substrate interaction and lack of its kinase activity induces prostate cells to acquire a malignant, migrating phenotype. J. Cell. Physiol. 209: 74–80, 2006. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Proline-rich tyrosine kinase 2 (Pyk2) expression in prostate epithelium inversely correlated with degree of malignancy of prostate cancers, thus the role of Pyk2 in the regulation of prostate cells proliferation and differentiation was investigate in PC3 cells. Pyk2 can be activated by canonic stimuli such as tumor necrosis factorα and lysophosphatidic acid (LPA) in PC3 cells, in addition, LPA stimulated Pyk2 phosphorylation also induced extracellular signal-regulated kinase 1 and 2 activation in these cells. Proliferation of PC3 cell clones (PC3-PKM) expressing a dominant negative kinase-defective Pyk2 mutant is consistently decreased in respect to that of wild type PC3 cells. In addition, PC3-PKM clones underwent total block cell proliferation upon treatment with dibutyryl cAMP. Finally, in the presence of sustained levels of intracellular cAMP, PC3-PKM cells, but not wild type PC3 cells, acquired a neuron-like morphology. Taken together our results suggest that Pyk2 plays a role in the regulation of prostate cell proliferation and, more interestingly, its expression may represents a sensitive marker of prostate state of differentiation. [Copyright &y& Elsevier]