An inverse association between cancer and neurodegeneration is plausible because these biological processes share several genes and signaling pathways. Whereas uncontrolled cell proliferation and decreased apoptotic cell death governs cancer, excessive apoptosis contributes to neurodegeneration. Protein kinase R (PKR), an interferon-inducible double-stranded RNA protein kinase, is involved in both diseases. PKR activation blocks global protein synthesis through eIF2α phosphorylation, leading to cell death in response to a variety of cellular stresses. However, PKR also has the dual role of activating the nuclear factor κ-B pathway, promoting cell proliferation. Whereas PKR is recognized for its negative effects on neurodegenerative diseases, in part, inducing high level of apoptosis, the role of PKR activation in cancer remains controversial. In general, PKR is considered to have a tumor suppressor function, and some clinical data show a correlation between suppressed or inactivated PKR and a poor prognosis for several cancers. However, other studies show high PKR expression and activation levels in various cancers, suggesting that PKR might contribute to neoplastic progression. Understanding the cellular factors and signals involved in the regulation of PKR in these age-related diseases is relevant and may have important clinical implications. The present review highlights the current knowledge on the role of PKR in neurodegeneration and cancer, with special emphasis on its regulation and clinical implications.

Recent meta-analysis indicate that coffee consumption may reduce the risk for digestive tract cancers (oral, esophageal, gastric and colorectal) and, especially, liver cancer. Coffee bean-derived beverages, such as the widely-consumed espresso and "common" filtered brews, are commodities of remarkable historical, cultural and economic importance globally. These drinks display rich and variable chemical composition, depending on many factors that vary from "seeding to serving". The alkaloids caffeine and trigonelline, and the polyphenol chlorogenic acid seem to be some of the most important bioactive organic compounds of these beverages, displaying high levels in both espresso and common brews and/or increased bioavailability after consumption. Thus, we proposed a comprehensive literature overview of current knowledge on the effects of coffee beverages and their highly bioavailable compounds, describing: 1) recent epidemiological and experimental findings highlighting the beneficial effects against gastrointestinal and liver carcinogenesis; and 2) the main molecular mechanisms in these in vitro and in vivo bioassays. Findings predominantly address protective effects of coffee and its most common and bioavailable compounds individually against gastrointestinal and liver cancer development. Our review underscores the complex effects of coffee on carcinogenesis, considering that beneficial effects are not limited to the whole beverage or selected compounds. Thus, this review should provide new insights of clinical and translational significance for further mechanistic investigations.

SIRT1, the closest mammalian homolog of yeast Sir2, is an NAD þ -dependent deacetylase with relevant functions in cancer, aging, and metabolism among other processes. SIRT1 has a diffuse nuclear localization but is recruited to the PML nuclear bodies (PML-NBs) after PML upregulation. However, the functions of SIRT1 in the PML-NBs are unknown. In this study we show that primary mouse embryo fibroblasts lacking SIRT1 contain reduced PML protein levels that are increased after reintroduction of SIRT1. In addition, overexpression of SIRT1 in HEK-293 cells increases the amount of PML protein whereas knockdown of SIRT1 reduces the size and number of PML-NBs and the levels of PML protein in HeLa cells. SIRT1 stimulates PML sumoylation in vitro and in vivo in a deacetylase-independent manner. Importantly, the absence of SIRT1 reduces the apoptotic response of vesicular stomatitis virus-infected cells and favors the extent of this PML-sensitive virus replication. These results show a novel function of SIRT1 in the control of PML and PML-NBs. The tumor suppressor PML is the main and essential component of the nuclear bodies (NBs), the dynamic compartments that participate in a number of cellular processes, including apoptosis, transcriptional regulation, DNA repair, and protection against viral infection. 1,2 PML acts as a tumor suppressor, antagonizing initiation, promotion, and progression of tumors of various histological origins. 3 PML is also implicated in the regulation of infection by a variety of RNA viruses, adenoviruses, and human cytomegalovirus. 4-7 Its function is regulated by post-translational modifications such as phosphorylation, sumoylation, ubiquitination, and acetylation. However, only the sumoylation of PML has been shown as essential for the formation of the PML-NBs and a crucial process for PML-dependent apoptosis and transcriptional regulation. 8 In addition to PML, PML-NBs contain several other proteins, such as SP100, SUMO-1, pRB, p53, and lately, the NAD þ -dependent, type III, histone/protein deacetylase SIRT1. 9,10 SIRT1 is the best-characterized class III histone deacetylase in mammalian cells and the closest homolog to yeast Sir2. However, although most of SIRT1 functions are related to its enzymatic activity, deacetylation-independent activities of SIRT1 have also been proposed. 11-14 SIRT1 is involved in a wide spectrum of biological processes through diverse substrates such as the tumor suppressor p53, 9,15-17 the transcription factor NF-kB, 18 and the FOXO family of transcription factors. 12,14,19,20 Although SIRT1 has a diffuse nuclear localization, it is recruited to the PML-NBs after PML upregulation. However, the functional significance of this PML-SIRT1 interaction has not been addressed.In this report, we show that there is a correlation between the levels of SIRT1 and PML present in both primary and transfected cells. This positive regulation of PML levels by SIRT1 is mediated by an increase in the sumoylation of PML by SIRT1, in a deacetylation-independent manner. Functional sign...