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Radogna F.,University of Rome Tor Vergata | Radogna F.,Laboratoire Of Biologie Moleculaire Et Cellulaire Du Cancer Lbmcc | Albertini M.C.,Urbino University | De Nicola M.,University of Rome Tor Vergata | And 3 more authors.
Mitochondrion | Year: 2015

Extra-neurological functions of melatonin include control of the immune system and modulation of apoptosis. We previously showed that melatonin inhibits the intrinsic apoptotic pathway in leukocytes via stimulation of high affinity MT1/MT2 receptors, thereby promoting re-localization of the anti-apoptotic Bcl-2 protein to mitochondria. Here we show that Bcl-2 sequesters pro-apoptotic Bax into mitochondria in an inactive form after melatonin treatment, thus reducing cell propensity to apoptosis. Bax translocation and the anti-apoptotic effect of melatonin are strictly dependent on the presence of Bcl-2, and on the 5-lipoxygenase (5-LOX) metabolite 5-hydroxyeicosatetraenoic acid (5-HETE), which we have previously shown to be produced as a consequence of melatonin binding to its low affinity target calmodulin. Therefore, the anti-apoptotic effect of melatonin requires the simultaneous, independent interaction with high (MT1/MT2) and low (calmodulin) affinity targets, eliciting two independent signal transduction pathways converging into Bax sequestration and inactivation. MT1/MT2 vs. lipoxygenase pathways are activated by 10-9 vs. 10-5M melatonin, respectively; the anti-apoptotic effect of melatonin is achieved at 10-5M, but drops to 10-9M upon addition of exogenous 5-HETE, revealing that lipoxygenase activation is the rate-limiting pathway. Therefore, in areas of inflammation with increased 5-HETE levels, physiological nanomolar concentrations of melatonin may suffice to maintain leukocyte viability. © 2015 © Elsevier B.V. and Mitochondria Research Society.

Valente S.,University of Rome La Sapienza | Liu Y.,Emory University | Schnekenburger M.,Laboratoire Of Biologie Moleculaire Et Cellulaire Du Cancer Lbmcc | Zwergel C.,University of Rome La Sapienza | And 20 more authors.
Journal of Medicinal Chemistry | Year: 2014

DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line. © 2014 American Chemical Society.

Cerella C.,Laboratoire Of Biologie Moleculaire Et Cellulaire Du Cancer Lbmcc | Grandjenette C.,Laboratoire Of Biologie Moleculaire Et Cellulaire Du Cancer Lbmcc | Dicato M.,Laboratoire Of Biologie Moleculaire Et Cellulaire Du Cancer Lbmcc | Diederich M.,Seoul National University
Current Drug Targets | Year: 2016

Cancer and aging are two similar processes representing the final outcome of timedependent accumulation of various irreversible dysfunctions, mainly caused by stress-induced DNA and cellular damages. Apoptosis and senescence are two types of cellular response to damages that are altered in both cancer and aging, albeit through different mechanisms. Carcinogenesis is associated with a progressive reduction in the ability of the cells to trigger apoptosis and senescence. In contrast, in aging tissues, there is an increased accumulation of senescent cells, and the nature of apoptosis deregulation varies depending on the tissue. Thus, the prevailing model suggests that apoptosis and cellular senescence function as two essential tumor-suppressor mechanisms, ensuring the health of the individual during early and reproductive stages of life, but become detrimental and promote aging later in life. The recent discovery that various anticancer agents, including canonical inducers of apoptosis, act also as inducers of cellular senescence indicates that pro-senescence strategies may have applications in cancer prevention therapy. Therefore, dissection of the mechanisms mediating the delicate balance between apoptosis and cellular senescence will be beneficial in the therapeutic exploitation of both processes in the development of future anticancer and anti-aging strategies, including minimizing the side effects of such strategies. Here, we provide an overview of the roles of apoptosis and cellular senescence in cancer and aging. © 2016 Bentham Science Publishers.

De Bosscher K.,Ghent University | Beck I.M.,Ghent University | Dejager L.,VIB | Dejager L.,Ghent University | And 13 more authors.
Cellular and Molecular Life Sciences | Year: 2014

Glucocorticoids (GCs) block inflammation via interference of the liganded glucocorticoid receptor (GR) with the activity of pro-inflammatory transcription factors NF-κB and AP-1, a mechanism known as transrepression. This mechanism is believed to involve the activity of GR monomers. Here, we explored how the GR monomer-favoring Compound A (CpdA) affects AP-1 activation and activity. Our results demonstrate that non-steroidal CpdA, unlike classic steroidal GCs, blocks NF-κB- but not AP-1-driven gene expression. CpdA rather sustains AP-1-driven gene expression, a result which could mechanistically be explained by the failure of CpdA to block upstream JNK kinase activation and concomitantly also phosphorylation of c-Jun. In concordance and in contrast to DEX, CpdA maintained the expression of the activated AP-1 target gene c-jun, as well as the production of the c-Jun protein. As for the underlying mechanism, GR is a necessary intermediate in the CpdA-mediated gene expression of AP-1-regulated genes, but seems to be superfluous to CpdA-mediated JNK phosphorylation prolongation. The latter phenomenon concurs with the inability of CpdA to stimulate DUSP1 gene expression. ChIP analysis demonstrates that DEX-activated GR, but not CpdA-activated GR, is recruited to AP-1-driven promoters. Furthermore, in mice we observed that CpdA instigates a strong enhancement of TNF-induced AP-1-driven gene expression. Finally, we demonstrate that this phenomenon coincides with an increased sensitivity towards TNF lethality, and implicate again a role for JNK2. In conclusion, our data support the hypothesis that a ligand-induced differential conformation of GR yields a different transcription factor cross-talk profile. © 2013 The Author(s).

Gaascht F.,Laboratoire Of Biologie Moleculaire Et Cellulaire Du Cancer Lbmcc | Dicato M.,Laboratoire Of Biologie Moleculaire Et Cellulaire Du Cancer Lbmcc | Diederich M.,Seoul National University
Genes and Nutrition | Year: 2015

Coffee is the second most popular beverage in the world after water with a consumption of approximately two billion cups per day. Due to its low cost and ease of preparation, it is consumed in almost all countries and by all social classes of the population through different modes of preparation. Despites its simple appearance, a cup of coffee is in fact a complex mixture that contains hundreds of molecules, the composition and concentration of which vary widely and depend on factors including the origin of the coffee tree or its metabolism. Although an excessive consumption of coffee can be harmful, many molecules that are present in this black decoction exert anticancer properties. This review aims to describe the different primary coffee-containing substances that exert chemopreventive and bioactive activities against the different hallmarks and enabling characteristics of cancer, thus explaining the anticancer health benefit of black coffee. © 2015, Springer-Verlag Berlin Heidelberg.

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