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Abstract: Pancreatic cancer is an aggressive malignancy with proclivity to early metastasis. High expression and activation of the collagenase matrix metalloproteinase-2 (MMP-2) have been found in human pancreatic cancer tissues, being these increased levels of active MMP-2 correlated to tumor invasion and metastasis. Hypoxia and reoxygenation (H–R) are critical pathophysiological conditions during ischemia–reperfusion injury, which has been shown to enhance both invasion and metastasis. In the present study, we investigated the effects of H–R on MMP-2 levels and the invasiveness properties of human pancreatic cancer cells PANC-1. Using specific inhibitors, we found that H–R treatment of these tumor cells induced secretion and activation of MMP-2, which was required for H–R-stimulated basement membrane degradation and cell invasion. Our results also indicate that signaling events involved in H–R-enhanced PANC-1 invasiveness comprehend PI3K-dependent activation of Rac1, which mediated the formation of NADPH-generated reactive oxygen species responsible for MMP-2 secretion and activation. [Copyright &y& Elsevier]

Abstract: Cancer metastasis involves tumor cells invading the surrounding tissue. Remodeling of tissue barriers depends on the ability of tumor cells to degrade the surrounding collagen matrix and then migrate through the matrix defects. Epidermal growth factor (EGF) has been shown to regulate tumor cell invasion through activation of matrix metalloproteinase-2 (MMP-2) in various tumor cell types. In the present study, we investigated the role of MMP-2 and the signaling pathway involved in EGF-promoted invasion by human pancreatic cancer cells PANC-1. Using specific inhibitors, we found that EGF stimulation of these tumor cells induced secretion and activation of the collagenase MMP-2, which was required for EGF-stimulated basement membrane degradation and cell invasion. Our results also indicate that signaling events downstream of EGF receptor involved PI3K- and Src-dependent activation of Rac1, which mediated the NADPH-generated reactive oxygen species responsible for MMP-2 secretion and activation. [Copyright &y& Elsevier]

Abstract: 6-Formylpterin (6FP) has the potential to produce singlet oxygen (1O2) under UV-A radiation. In order to apply this potential to anti-cancer photodynamic therapy (PDT), we prepared a novel variant of 6FP, 2-(N,N-dimethylaminomethyleneamino)-6-formyl-3-pivaloylpteridine-4-one (6FP-tBu-DMF), and examined its photodynamic effects on a pancreatic cancer cell line, Panc-1 cells. The study using laser scanning confocal microscopy showed that the drug uptake, the 1O2 generation, and cell death were observed in the 6FP-tBu-DMF-treated cells, while these phenomena were not observed in the 6FP-treated cells. The MTT assay also showed the decrease in cell viability only in the 6FP-tBu-DMF-treated cells. Since 6FP and 6FP-tBu-DMF generate 1O2 to the same extent under UV-A radiation in aqueous solutions, these results indicated that the differences in the photodynamic effects between 6FP and 6FP-tBu-DMF were entirely attributed to the differences in the cell permeability between them. The development of cell permeable pterin derivatives has the potential for application in PDT. [Copyright &y& Elsevier]

The protein kinase D (PKD) family consists of three serine/threonine protein kinases: PKCμ/PKD, PKD2, and PKCν/PKD3. While PKD has been the focus of most studies to date, no information is available on the intracellular distribution of PKD2. Consequently, we examined the mechanism that regulates its intracellular distribution in human pancreatic carcinoma Panc-1 cells. Analysis of the intracellular steady-state distribution of fluorescent-tagged PKD2 in unstimulated cells indicated that this kinase is predominantly cytoplasmic. Cell stimulation with the G protein-coupled receptor agonist neurotensin induced a rapid and reversible plasma membrane translocation of PKD2 by a mechanism that requires PKC activity. In contrast to the other PKD isoenzymes, PKD2 activation did not induce its redistribution from the cytoplasm to the nucleus. Thus, this study demonstrates that the regulation of the distribution of PKD2 is distinct from other PKD isoenzymes, and suggests that the differential spatio-temporal localization of these signaling molecules regulates their specific signaling properties. [Copyright &y& Elsevier]