Data di Pubblicazione:
2011
Citazione:
ROLE OF DIHYDROCERAMIDE IN CELL SIGNALING / V. Gagliostro ; tutore: Paola Signorelli ; direttore : Mario Clerici. Universita' degli Studi di Milano, 2011 Jun 06. 23. ciclo, Anno Accademico 2010. [10.13130/gagliostro-vincenzo_phd2011-06-06].
Abstract:
Sphingolipids are a class of bioactive lipids. Ceramide is the hub molecule of the
intricate sphingolipid biosynthetic pathway. It is a bioactive lipid, regulating a
number of physiological functions such as apoptosis, cell growth arrest,
differentiation, senescence, migration and adhesion. The dihydroceramide is the
precursor of ceramide along the de novo biosynthetic pathway. Several groups
considered the dihydroceramide an inactive molecule. Recent studies associated
dihydroceramide with the induction of cellular processes such as cell cycle arrest
and programmed cell death. On the other hand this molecule also showed antiapoptotic
properties. The goal of my doctorate project is to demonstrate the
dihydroceramide implication in the regulation of a pro-survival cell response to
stress. Hence, the human gastric carcinoma HGC-27 cells were treated with
resveratrol, a molecule that induces dihydroceramide accumulation. Resveratrol is
a polyphenol with well known anti-oxidant and anti-tumoral properties. On the other
hand it is a calorie restriction mimetic, thus it activates sirtuins, promoting cell
survival. A number of studies demonstrated that resveratrol modulates the
biosynthetic de novo pathway of ceramide. Here we demonstrated that resveratrol,
similarly to the specific inhibitor XM462, inhibits DEGS-1 desaturase activity,
inducing dihydroceramide accumulation. This accumulation results in autophagy
induction without affecting cell viability. We also obtained this response treating
different cell lines with several drugs or conditions known to induce
dihydroceramide accumulation. Although autophagy did not affect cell viability,
however it causes a delay in cell proliferation. In fact we demonstrated that
dihydroceramide accumulation in HGC-27 cells induces a temporary arrest in
G0/G1 phase resulting in the delayed cell cycle phases progression. Moreover, we
demonstrated that both autophagy activation and cell cycle arrest are temporally
subsequent to the unfolded protein response (UPR) which is due to the
dihydroceramide accumulation-mediated ER stress. All these results give an
important contribute to the understanding of the metabolic role of sphingolipid
mediators and their targeting in the anti-tumoral therapy.
Tipologia IRIS:
Tesi di dottorato
Keywords:
sfingolipidi ; autofagia ; cancro
Elenco autori:
V. Gagliostro
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