Transformation by the K-RAS oncogene correlates with increases in phospholipase A2 activity, glycerophosphoinositol production and phosphoinositide synthesis in thyroid cells

Valitutti, Salvatore; Cucchi, Paola; Colletta, Giulia; Filippo, Carmine Di; Corda, Daniela

doi:10.1016/0898-6568(91)90061-x

Cited by 45 publications

(57 citation statements)

References 35 publications

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“…PIs, which are phosphoinositide metabolites, are catalyzed by phospholipase A2 and a lysophospholipase, which are known to be RASdependent (45). Lysophospholipase catalyzes the production of PI from phosphoinositides, a process which is greatly augmented by RAS transformation in both fibroblasts and other cells, indicating the importance of glycerophospholipid metabolism in RAS (46)(47)(48). Our results could reflect that generally specific oncogenes will be associated with unique lipid signatures.…”

Section: Discussionmentioning

confidence: 73%

Alteration of the lipid profile in lymphomas induced by MYC overexpression

Eberlin

Gabay

Fan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

121

103

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Overexpression of the v-myc avian myelocytomatosis viral oncogene homolog (MYC) oncogene is one of the most commonly implicated causes of human tumorigenesis. MYC is known to regulate many aspects of cellular biology including glucose and glutamine metabolism. Little is known about the relationship between MYC and the appearance and disappearance of specific lipid species. We use desorption electrospray ionization mass spectrometry imaging (DESI-MSI), statistical analysis, and conditional transgenic animal models and cell samples to investigate changes in lipid profiles in MYC-induced lymphoma. We have detected a lipid signature distinct from that observed in normal tissue and in rat sarcoma-induced lymphoma cells. We found 104 distinct molecular ions that have an altered abundance in MYC lymphoma compared with normal control tissue by statistical analysis with a false discovery rate of less than 5%. Of these, 86 molecular ions were specifically identified as complex phospholipids. To evaluate whether the lipid signature could also be observed in human tissue, we examined 15 human lymphoma samples with varying expression levels of MYC oncoprotein. Distinct lipid profiles in lymphomas with high and low MYC expression were observed, including many of the lipid species identified as significant for MYC-induced animal lymphoma tissue. Our results suggest a relationship between the appearance of specific lipid species and the overexpression of MYC in lymphomas.biostatistics | transgenic models | lipidomics | metabolomics | cancer T he v-myc avian myelocytomatosis viral oncogene homolog (MYC) is commonly overexpressed in human neoplasia (1, 2) and has been strongly associated with the clinical aggressiveness of human cancers (3, 4). MYC is particularly associated with the pathogenesis of hematopoietic tumors such as lymphomas and of epithelial tumors (5, 6). In Burkitt's lymphoma, for example, the c-Myc gene is translocated to one of the Ig loci in virtually all tumors (5,7,8). The MYC oncogene contributes to tumorigenesis by functioning as a global regulator of transcription involving many cellular programs, including cellular growth, metabolism, and lipid synthesis (9, 10). MYC induces a global shift in metabolism associated with anaerobic glycolysis, a phenomenon known as the Warburg effect (11). Several studies have shown a relationship between MYC regulation and metabolism in lymphomas, especially as related to the processes of glycolysis and glutaminolysis (12, 13). Some reports suggest that MYC regulates fatty acid synthesis, specifically palmitate (14); however, little is known about the relationship between MYC expression and the up-regulation or down-regulation of various lipid species in lymphomas.We have generated transgenic mice to conditionally regulate expression of MYC oncogenes alone or in combination with oncogenes such as rat sarcoma (RAS), BCR-ABL, and BCL2 to produce many transgenic models of cancers, including T-cell acute lymphocytic leukemia, acute myeloid leukemia, osteosarcoma, lung adenocarc...

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Section: Discussionmentioning

confidence: 73%

Alteration of the lipid profile in lymphomas induced by MYC overexpression

Eberlin

Gabay

Fan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

121

103

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“…The cellular levels of some of these phosphoinositide derivatives have been shown to be altered during Rasmediated cell transformation in a number of cell lines (Alonso et al, 1988;Valitutti et al, 1991;Corda and Falasca, 1996;Falasca and Corda, 1994;Falasca et al, 1995). In particular, high levels of both lysophosphatidylinositol (LysoPtdIns), a molecule generated by a constitutively-active phosphoinositide (PtdIns)-speci®c phospholipase A 2 , and of glycerophosphoinositols (derived from LysoPtdIns through a second deacylation step) have been reported in cells of dierent origin transformed by the ras oncogene (Alonso et al, 1988;Valitutti et al, 1991;Iacovelli et al, 1993;Corda and Falasca, 1996;Falasca and Corda, 1994;Falasca et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

“…Other phosphoinositide derivatives of potential biological relevance include those involved in the phosphatidylinositol 3-kinase pathway (Panayotou and Water®eld, 1992), the inositol polyphosphates (Sasakawa et al, 1995), the cyclic inositols (Majerus et al, 1988), the glycerophosphoinositols (Alonso et al, 1988;Valitutti et al, 1991;Iacovelli et al, 1993;Corda and Falasca, 1996) and lysophosphatidylinositol (Falasca and Corda, 1994;Falasca et al, 1995;Metz, 1986;Baran and Kelly, 1987).…”

Section: Introductionmentioning

confidence: 99%

Release of the mitogen lysophosphatidylinositol from H-Ras-transformed fibroblasts; a possible mechanism of autocrine control of cell proliferation

et al. 1998

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Lysophosphatidylinositol (LysoPtdIns) is formed by a constitutively-active phosphoinositide-speci®c phospholipase A 2 in Ras-transformed cells and can stimulate cell proliferation. To evaluate whether LysoPtdIns could function as an autocrine modulator of cell growth, we examined whether LysoPtdIns can be released in the medium of Ras-transformed FRT-Fibro ®broblasts and thyroid cells. Here, we report that LysoPtdIns accumulates in the extracellular space of these lines and reaches levels up to tenfold higher than in the case of normal cells. Moreover, the ionophore A23187 increased the levels of the lysolipid in the extracellular medium. Extracellular LysoPtdIns was rapidly hydrolyzed to inositol 1 : 2-cyclic phosphate. LysoPtdIns induced thymidine incorporation in FRT-Fibro Ha-Ras ®bro-blasts, whereas inositol cyclic 1 : 2-cyclic phosphate did not aect cell growth per se, nor did it interfere with the LysoPtdIns mitogenic activity. We hypothesize that in Ras-transformed ®broblasts the formation and release of LysoPtdIns may function as an autocrine mechanism that participates in the Ras-dependent stimulation of cell growth.

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“…These molecules have been associated with the expression of oncogenic Ras (Alonso et al, 1988;Alonso and Santos, 1990;Valitutti et al, 1991;Falasca et al, 1995) and are biologically active. Lysophosphatidylinositol acts as a mitogen in Rastransformed cells (Falasca and Corda, 1994;Falasca et al, 1995Falasca et al, , 1998, and among the glycerophosphoinositols, glycerophosphoinositol 4-phosphate (GroPIns-4P) has been shown to inhibit the heterotrimeric G protein Gs in thyroid cells, thereby decreasing the cellular levels of cAMP and inhibiting cAMPdependent functions, such as cell proliferation and iodide uptake (Iacovelli et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Reorganization of Actin Cytoskeleton by the Phosphoinositide Metabolite Glycerophosphoinositol 4-Phosphate

Mancini

Piccolo

Mariggiò

et al. 2003

MBoC

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Glycerophosphoinositol 4-phosphate (GroPIns-4P) is a biologically active, water-soluble phospholipase A metabolite derived from phosphatidylinositol 4-phosphate, whose cellular concentrations have been reported to increase in Ras-transformed cells. It is therefore important to understand its biological activities. Herein, we have examined whether GroPIns-4P can regulate the organization of the actin cytoskeleton, because this could be a Ras-related function involved in cell motility and metastatic invasion. We find that in serum-starved Swiss 3T3 cells, exogenously added GroPIns-4P rapidly and potently induces the formation of membrane ruffles, and, later, the formation of stress fibers. These actin structures can be regulated by the small GTPases Cdc42, Rac, and Rho. To analyze the mechanism of action of GroPIns-4P, we selectively inactivated each of these GTPases. GroPIns-4P requires active Rac and Rho, but not Cdc42, for ruffle and stress fiber formation, respectively. Moreover, GroPIns-4P induces a rapid translocation of the green fluorescent protein-tagged Rac into ruffles, and increases the fraction of GTP-bound Rac, in intact cells. The activation of Rac by GroPIns-4P was near maximal and long-lasting. Interestingly, this feature seems to be critical in the induction of actin ruffles by GroPIns-4P.

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Transformation by the K-RAS oncogene correlates with increases in phospholipase A2 activity, glycerophosphoinositol production and phosphoinositide synthesis in thyroid cells

Cited by 45 publications

References 35 publications

Alteration of the lipid profile in lymphomas induced by MYC overexpression

Alteration of the lipid profile in lymphomas induced by MYC overexpression

Release of the mitogen lysophosphatidylinositol from H-Ras-transformed fibroblasts; a possible mechanism of autocrine control of cell proliferation

Reorganization of Actin Cytoskeleton by the Phosphoinositide Metabolite Glycerophosphoinositol 4-Phosphate

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