SPHINGOLIPID METABOLISM'S ALTERATIONS CORRELATED WITH TUMOR CELL INVASIVITY AND FENRETINIDE RESISTANCE IN A HUMAN OVARIAN CARCINOMA CELL LINE
Tesi di Dottorato
Data di Pubblicazione:
2010
Citazione:
SPHINGOLIPID METABOLISM'S ALTERATIONS CORRELATED WITH TUMOR CELL INVASIVITY AND FENRETINIDE RESISTANCE IN A HUMAN OVARIAN CARCINOMA CELL LINE / G. Illuzzi ; Docente Guida: Alessandro Prinetti ; Tutor: Sandro Sonnino ; Coordinatore: Francesco Bonomi. Università degli Studi di Milano, 2010 Dec 09. 23. ciclo, Anno Accademico 2010. [10.13130/illuzzi-giuditta_phd2010-12-09].
Abstract:
Glycosphingolipids (GSL) modulate several signal transduction processes controlling cell proliferation, survival, differentiation and transformation. Alterations in the expression of carbohydrate epitopes associated with GSL are frequent in tumors, and it has been hypothesized that GSL could play important roles in modulating some of the properties of tumor cells. The contribution of transformation-associated changes in GSL composition to the tumor phenotype are very complex and not fully elucidated, and likely implies heterogeneous molecular mechanisms. However, at least two well established paradigms support this role: 1) gangliosides have been described as modulators of growth factor receptor function, associated tyrosine kinase activities and cellular compartmentalization. 2) GM3 and/or GM2 inhibit integrin-dependent tumor cell motility via the formation of a ganglioside/tetraspanin/integrin receptor complex (the “glycosynapse”) that is responsible for the negative regulation of c-Src tyrosine kinase activity [1].
In addition, several commonly used anticancer drugs exert their cytotoxic action at least in part by triggering the production of the sphingolipid ceramide, a mediator of apoptosis and an inhibitor of cell proliferation in a variety of tumor cell lines [2]. It has been demonstrated that chemoresistant tumor and tumor cell lines are frequently characterized by the increased glycosylation of ceramide with formation of glucosylceramide, due to an increased expression or activation of glucosylceramide synthase (GCS) [3]. Scavenging ceramide via its increased glycosylation would allow tumor cells to escape ceramide-induced apoptosis, thus contributing to the drug resistant phenotype [4-6]. However, it has been shown that GlcCer accumulation is not the only consequence of an altered sphingolipid metabolism in drug resistant cancer cells. In addition to its use as a precursor of complex sphingolipids, ceramide can be converted into sphingosine, which is then phosphorylated from sphingosine kinases to generate sphingosine 1-phosphate (S1P). Up-regulation of sphingosine kinase and concomitant decrease of the levels of sphingolipid mediators upstream to sphingosine kinase have been associated with resistance to camptothecin and docetaxel in prostate cancer cells [7, 8], to oxaliplatin in colon cancer cells [9] and to gemcitabine in pancreatic cancer cells [10].
During my PhD period, I have studied the alterations in sphingolipid metabolism and their functional relevance in different phenotypic variants of a human ovarian carcinoma cell line, A2780. A2780 cells are sensitive to a variety of antitumor drugs, including the synthetic retinoid N-(4-hydroxyphenyl)retinamide (fenretinide or HPR), that is currently it is under clinical trials as preventive chemotherapeutic drug for prostatic and ovarian cancer, neuroblastoma, lymphoma and leukemia. A2780/HPR is a HPR-resistant cell line obtained from the parental A2780 cell line by in vitro exposure to increasing sublethal HPR concentrations. The A2780/HPR cell line presents a multiple phenotypic differences compared to A2780 cells. Previous work from this lab showed that A2780/HPR cells express higher ganglioside levels respect to the parental cell line, due to the overexpression of GM3 synthase, a key enzyme in ganglioside biosynthetic pathway, and a higher sphingolipid degradation rate [11].
In addition to HPR resistance, A2780/HPR cells are characterized by a reduced in vitro motility respect to the parental cell line. Subsequent experiments were aimed at elucidating a possible link between alterations in sphingolipid metabolism and modulation of cell motility and/or the acquisition of resistance to HPR. At first, we examined the effect of the overexpression of sialyltran
Tipologia IRIS:
Tesi di dottorato
Keywords:
OVARIAN CARCINOMA CELL LINE ; FENRETINIDE ; DRUG RESISTANCE ; CELL MOTILITY ; SPHINGOSINE KINASE-1
Elenco autori:
G. Illuzzi
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