Ca2+ Signaling and Its Potential Targeting in Pancreatic Ductal Carcinoma.

Pancreatic cancer (PC) is a major cause of cancer-associated mortality in Western countries (and estimated to be the second cause of cancer deaths by 2030). The main form of PC is pancreatic adenocarcinoma, which is the fourth most common cause of cancer-related death, and this situation has remained virtually unchanged for several decades. Pancreatic ductal adenocarcinoma (PDAC) is inherently linked to the unique physiology and microenvironment of the exocrine pancreas, such as pH, mechanical stress, and hypoxia. Of them, calcium (Ca2+) signals, being pivotal molecular devices in sensing and integrating signals from the microenvironment, are emerging to be particularly relevant in cancer. Mutations or aberrant expression of key proteins that control Ca2+ levels can cause deregulation of Ca2+-dependent effectors that control signaling pathways determining the cells' behavior in a way that promotes pathophysiological cancer hallmarks, such as enhanced proliferation, survival and invasion. So far, it is essentially unknown how the cancer-associated Ca2+ signaling is regulated within the characteristic landscape of PDAC. This work provides a complete overview of the Ca2+ signaling and its main players in PDAC. Special consideration is given to the Ca2+ signaling as a potential target in PDAC treatment and its role in drug resistance.

The Neuroinflammatory and Neurotoxic Potential of Palmitic Acid Is Mitigated by Oleic Acid in Microglial Cells and Microglial-Neuronal Co-cultures.

Neuroinflammation has been implicated in the pathogenesis of neurodegeneration and is now accepted as a common molecular feature underpinning neuronal damage and death. Palmitic acid (PA) may represent one of the links between diet and neuroinflammation. The aims of this study were to assess whether PA induced toxicity in neuronal cells by modulating microglial inflammatory responses and/or by directly targeting neurons. We also determined the potential of oleic acid (OA), a monounsaturated fatty acid, to counteract inflammation and promote neuroprotection. We measured the ability of PA to induce the secretion of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), the induction of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathways, as well as the phosphorylation of c-Jun, and the expression of inducible nitric oxide synthase (iNOS). Finally, to determine whether PA exerted an indirect neurotoxic effect on neuronal cells, we employed a microglia-neuron co-culture paradigm where microglial cells communicate with neuronal cells in a paracrine fashion. Herein, we demonstrate that PA induces the activation of the NF-κB signalling pathway and c-Jun phosphorylation in N9 microglia cells, in the absence of increased cytokine secretion. Moreover, our data illustrate that PA exerts an indirect as well as a direct neurotoxic role on neuronal PC12 cells and these effects are partially prevented by OA. These results are important to establish that PA interferes with neuronal homeostasis and suggest that dietary PA, when consumed in excess, may induce neuroinflammation and possibly concurs in the development of neurodegeneration.