1,721,361 research outputs found
Endoplasmic Reticulum Stress, Unfolded Protein Response, and Cancer Cell Fate
Full text linkPerturbation of endoplasmic reticulum (ER) homeostasis results in a stress condition termed "ER stress" determining the activation of a finely regulated program defined as unfolded protein response (UPR) and whose primary aim is to restore this organelle's physiological activity. Several physiological and pathological stimuli deregulate normal ER activity causing UPR activation, such as hypoxia, glucose shortage, genome instability, and cytotoxic compounds administration. Some of these stimuli are frequently observed during uncontrolled proliferation of transformed cells, resulting in tumor core formation and stage progression. Therefore, it is not surprising that ER stress is usually induced during solid tumor development and stage progression, becoming an hallmark of such malignancies. Several UPR components are in fact deregulated in different tumor types, and accumulating data indicate their active involvement in tumor development/progression. However, although the UPR program is primarily a pro-survival process, sustained and/or prolonged stress may result in cell death induction. Therefore, understanding the mechanism(s) regulating the cell survival/death decision under ER stress condition may be crucial in order to specifically target tumor cells and possibly circumvent or overcome tumor resistance to therapies. In this review, we discuss the role played by the UPR program in tumor initiation, progression and resistance to therapy, highlighting the recent advances that have improved our understanding of the molecular mechanisms that regulate the survival/death switch. © 2017 Corazzari, Gagliardi, Fimia and Piacentini
ER Stress & Autophagy in Cancer: Contenders or Partners in Crime?
No full textTumour development and progression are associated to a variety of events
responsible for normal cell transformation, resulting in uncontrolled cell
proliferation, tumour core formation, vascularization and, finally, tumour cell
dissemination. Although oncogenic transformation represents the first episode
responsible for tumour initiation, secondary events are also required to sustain
cancer cell growth and survival, and inhibit cell death. ER stress and
autophagy are two physiological pathways activated by cells under stress
conditions, primarily to cope with stress and ensure cell survival, although
unresolved or acute stress may shift pro-survival into pro-deathsignalling of
both pathways. Since autophagy may represent a barrier against cell
transformation, established tumours cells induce both autophagy and ER
stress in response to metabolic stress to promote survival. Autophagy
induction is also stimulated by the unfolded protein response (UPR) under ER
stress conditions and, on the other hand, the former counterbalances ER
expansion during the UPR, indicating a close and intricate mutual crossregulation,
which is exploited by cancer cells to survive and inhibit death
stimuli, such as those of chemotherapeutic drugs
Wild-type and mutant p53 in cancer-related ferroptosis. A matter of stress management?
Full text linkCancer cells within tumor masses are chronically exposed to stress caused by nutrient deprivation, oxygen limitation, and high metabolic demand. They also accumulate hundreds of mutations, potentially generating aberrant proteins that can induce proteotoxic stress. Finally, cancer cells are exposed to various damages during chemotherapy. In a growing tumor, transformed cells eventually adapt to these conditions, eluding the death-inducing outcomes of signaling cascades triggered by chronic stress. One such extreme outcome is ferroptosis, a form of iron-dependent non-apoptotic cell death mediated by lipid peroxidation. Not surprisingly, the tumor suppressor p53 is involved in this process, with evidence suggesting that it acts as a pro-ferroptotic factor and that its ferroptosis-inducing activity may be relevant for tumor suppression. Missense alterations of the TP53 gene are extremely frequent in human cancers and give rise to mutant p53 proteins (mutp53) that lose tumor suppressive function and can acquire powerful oncogenic activities. This suggests that p53 mutation provides a selective advantage during tumor progression, raising interesting questions on the impact of p53 mutant proteins in modulating the ferroptotic process. Here, we explore the role of p53 and its cancer-related mutants in ferroptosis, using a perspective centered on the resistance/sensitivity of cancer cells to exogenous and endogenous stress conditions that can trigger ferroptotic cell death. We speculate that an accurate molecular understanding of this particular axis may improve cancer treatment options
The lexico-semantic annotation of an Italian Treebank
No full textIn this paper we present the lexico-semantic annotation of an Italian treebank, focusing on the annotation strategy followed, the results achieved, and possible further work and application
Limitation of continuous monitoring via TDR and EC in silty loamy soils to quantify groundwater recharge rates
No full textGroundwater recharge is one of the key factor of the
hydrological budget. Many methods could be used to have
reasonable estimates of this parameter like the water-balance
method, the water table fluctuation method or via numerical
simulations (NIMMO et alii, 2005). Usually these methods are
valid for watershed studies but need to be validated for site
specific applications. Tracer techniques for recharge
assessment are often time consuming and their laboratory costs
are quite elevated. A relatively cheap solution is to employ low
cost TDR probes to monitor the water content and the soil
electrical conductivity (NOBORIO et alii, 2001; MORTL et alii,
2011). The aim of this study is to evaluate the limitation of
continuous monitoring in determining groundwater recharge
rates in agricultural silty soils
Harnessing Autophagy for Melanoma Benefit
No full textCutaneous melanoma, the most aggressive form of skin cancer, remains one of the most difficult human cancers to treat, with an increasing incidence in developed countries which has risen faster than any other malignancy over the past 40 years. Melanoma occurs when the pigment-producing cells (melanocytes) within the basal epidermis become transformed due to both environmental and genetic risk factors. Although early stage disease is treatable through surgical excision alone, metastatic melanoma is highly invasive and evolves with an extensive repertoire of molecular defences against immunological and cytotoxic attack, rendering this type of tumour notoriously unresponsive to conventional
chemotherapy and leaving an acute need for novel therapeutic strategie
Why is autophagy important for melanoma? Molecular mechanisms and therapeutic implications
No full textAs the principle lysosomal mediated mechanism for the degradation of aged or damaged organelles and proteins, autophagy (self-eating) is generally considered a pro-survival process activated by cells to sustain life in presence of adverse environmental conditions such as nutrient shortage and/or in presence of cytotoxic compounds [1]. Upon activation, cytoplasmic material is sequestered into double-membrane vesicles (autophagosomes) then targeted for degradation by fusion with lysosomes (autolysosomes); metabolic activity and cell survival are consequently sustained by recycling the degradation products. Basal autophagy occurs in almost all cell types, though at different degree, as a finely regulated "quality control" process to prevent cell damage, for the demolition of cellular structures during cell/tissue remodelling, and to ensure the maintenance of cellular homeostasis through recycling cellular components/molecules [2,3]. Autophagy is stimulated in response to both physiological and pathological conditions such as starvation, hypoxia and low energy, pathogen infection and protein aggregates. Although it's clear that autophagy is also involved in cancer, its role, however, is complex since it can both suppress and promote tumorigenesis [4]. Consequently, it is generally accepted that while autophagy is used by advanced stage cancers to maintain tumour survival, loss of autophagy in earlier stages is associated with tumour development. Accordingly, it is now apparent that aberrant control of autophagy is among key hallmarks of cancer, with several studies now demonstrating this process is deregulated also in melanoma [5,6]
Merkel Cell Polyomavirus (MCV) in Buffy Coats of Healthy Blood Donors.
No full textBackground.
Merkel cell polyomavirus (MCV), a DNA tumor virus, has been found to be associated with Merkel cell carcinoma (MCC) and chronic lymphocytic leukaemia (CLL). MCV sequences have also been detected in various normal tissues in tumor affected patients. Immunologic studies have detected MCV antibodies in as many as 80% of healthy blood donors. This high seroprevalence suggests that MCV infection is widespread in humans.
Materials and methods
DNA from buffy coats (n=60) of healthy blood donors was investigated by two PCR rounds, 35 cycles each, for two different MCV Tag regions, nt 571-879 and nt 1709-1846, respectively. To quantify the MCV DNA load, positive samples were further analyzed by RQ-PCR for Tag sequences. To determine the human cell equivalents of each sample under analysis, RQ-PCR assays were carried out simultaneously with the cellular RNase P gene. The specificity of PCR amplified products, 10 amplicons from the MCV Tag regions, were DNA sequenced.
Results
PCR re-amplifications showed that 13 out of 60 (22%) DNA samples were positive for MCV Tag coding sequences. Buffy coats under analysis indicated that the viral DNA copy numbers were very low, ranging from 10 to 100 copies/100,000 cells. The sequencing result of the PCR amplicons, for both strands, nt 571-879 and nt 1709-nt 1846, identified as belonging to the MCV genome, MKL-1 strain.
Conclusions
MCV sequences were detected in buffy coats from healthy blood donors. This result suggests that MCV is able to infect specific blood leukocyte cells, where it remains in a latent/persistent state in the PBMCs of immune-competent individuals. In the long term, viral persistent infection may allow MCV to generate mutants which can participate in the cell transformation process. Indeed, large T antigen MCV deletion mutants have been detected in CLL or integrated into MCC. This oncogenic process, together with the immune impairment of the host and other factors, is a well-known multistep cell transformation mechanism employed by other DNA tumor viruses, such as human papillomaviruses, which are closely related to the Merkel cell polyomavirus.
Acknowledgements
We thank Prof. Tobias Allander, Karolinska Instituten, Stockolm, Sweden, for his generous gift of the recombinant plasmid pMCV-LT.1
Reference
Pancaldi C, Corazzari V, Maniero S, Mazzoni E, Comar M, Martini F, Tognon M. Merkel cell polyomavirus DNA sequences in the buffy coats of healthy blood donors. Blood 2011, 117:7099-7101
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