RETRACTED ARTICLE: Silencing of membrane-associated sialidase Neu3 diminishes apoptosis resistance and triggers megakaryocytic differentiation of chronic myeloid leukemic cells K562 through the increase of ganglioside GM3

Tringali, Cristina; Lupo, Barbara; Cirillo, Federica; Papini, Nadia; Anastasia, Luigi; Lamorte, Giuseppe; Colombi, Paolo; Bresciani, Roberto; Monti, Eugenio; Tettamanti, Guido; Venerando, Bruno

doi:10.1038/cdd.2008.141

Cited by 48 publications

(37 citation statements)

References 41 publications

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“…We also investigated changes in the expression of genes related to MK maturation/polyploidization: cyclin D1, cyclin D3, and p21. In primary megakaryocytes cyclin D3 is known to be a key driver of endomitotic cell cycling [35], while PMA-induced MK differentiation in K562 cells corresponds to dramatic increases in cyclin D1 and p21 [36]. Consistent with a reduction in cell cycling, we found that SIRT1 silencing resulted in a 130% increase in p21 levels (relative to the non-silencing control) after 3 days of PMA treatment (Fig.…”

Section: Resultssupporting

confidence: 67%

SIRT1 is a critical regulator of K562 cell growth, survival, and differentiation

Duncan¹,

DeLuca²,

Kuo³

et al. 2016

Experimental Cell Research

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Inhibition of histone deacetylases (HDACi) has emerged as a promising approach in the treatment of many types of cancer, including leukemias. Among the HDACs, Class III HDACs, also known as sirtuins (SIRTs), are unique in that their function is directly related to the cell’s metabolic state through their dependency on the co-factor NAD+. In this study, we examined the relation between SIRTs and the growth, survival, and differentiation of K562 erythroleukemia cells. Using a mass spectrometry approach we previously developed, we show that SIRT expression and deacetylase activity in these cells changes greatly with differentiation state (undifferentiated vs. megakaryocytic differentiation vs. erythroid differentiation). Moreover, SIRT1 is crucially involved in regulating the differentiation state. Overexpression of wildtype (but not deacetylase mutant) SIRT1 resulted in upregulation of glycophorin A, ~2-fold increase in the mRNA levels of α, γ, ε, and ζ - globins, and spontaneous hemoglobinization. Hemin-induced differentiation was also enhanced by (and depended on) higher SIRT1 levels. Since K562 cells are bipotent, we also investigated whether SIRT1 modulation affected their ability to undergo megakaryocytic (MK) differentiation. SIRT1 was required for commitment to the MK lineage and subsequent maturation, but was not directly involved in polyploidization of either K562 cells or an already-MK-committed cell line, CHRF-288-11. The observed blockage in commitment to the MK lineage was associated with a dramatic decrease in the formation of autophagic vacuoles, which was previously shown to be required for K562 cell MK commitment. Autophagy-associated conversion of the protein LC3-I to LC3-II was greatly enhanced by overexpression of wildtype SIRT1, further suggesting a functional connection between SIRT1, autophagy, and MK differentiation. Based on its clear effects on autophagy, we also examined the effect of SIRT1 modulation on stress responses. Consistent with results of prior studies, we found that SIRT1 silencing modestly promoted drug-induced apoptosis, while overexpression was protective. Furthermore, pan-SIRT inhibition mediated by nicotinamide pre-treatment substantially increased imatinib-induced apoptosis. Altogether, our results suggest a complex role for SIRT1 in regulating many aspects of K562 cell state and stress response. These observations warrant further investigation using normal and leukemic primary cell models. We further suggest that, ultimately, a well-defined mapping of HDACs to their substrates and corresponding signaling pathways will be important for optimally designing HDACi-based therapeutic approaches.

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Section: Resultssupporting

confidence: 67%

SIRT1 is a critical regulator of K562 cell growth, survival, and differentiation

Duncan¹,

DeLuca²,

Kuo³

et al. 2016

Experimental Cell Research

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“…BCR-ABL might be competing with ceramides for providing survival abilities to leukemic cells as shown by a study indicating Abl kinase as a negative regulator of Fas-mediated cell death which is a convergent pathway for ceramide signaling [208,209]. In addition to the importance of ceramides, some gangliosides (GM3 in particular here as well) were shown to be potent for inducing megakaryocytic differentiation of CML blasts [210,211]. Moreover, desialylation of some glycoproteins by Neu2, a cytosolic sialidase, might block BCR-ABL/Src signaling [212].…”

Section: Targeting Sphingolipid Metabolism For the Treatment Of Leukementioning

confidence: 99%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

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Sphingolipids are major constituents of the cells with emerging roles in the regulation of cellular processes. Deregulation of sphingolipid metabolism is reflected as various pathophysiological conditions including metabolic disorders and several forms of cancer. Ceramides, ceramide-1-phosphate (C1P), glucosyl ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P) are among the bioactive sphingolipid species that have important roles in the regulation of cell death, survival and chemotherapeutic resistance. Some of those species are known to accumulate in the cells upon chemotherapy while some others are known to exhibit an opposite pattern. Even though the length of fatty acid chain has a deterministic effect, in general, upregulation of ceramides and sphingosine is known to induce apoptosis. However, S1P, C1P and GluCer are proliferative for cells and they are involved in the development of chemoresistance. Therefore, sphingolipid metabolism appears as a good target for the development of novel therapeutics or supportive interventions to increase the effectiveness of the chemotherapeutic drugs currently in hand. Some approaches involve manipulation of the synthesis pathways yielding the increased production of apoptotic sphingolipids while the proliferative ones are suppressed. Some others are trying to take advantage of cytotoxic sphingolipids like short chain ceramide analogs by directly delivering them to the malignant cells as a distinct chemotherapeutic intervention. Numerous studies in the literature show the feasibility of those approaches especially in acute and chronic leukemias. This review compiles the current knowledge about sphingolipids and their roles in chemotherapeutic response with the particular attention to leukemias.

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“…Sialidase Activity Assay-The sialidase activity that was present in the particulate fraction of the mock and NEU3-silenced CA-TC and GR-TC cells was assayed using [ 3 H]GD1a at pH 3.8 as previously reported (13). One unit of sialidase activity is defined as the amount of enzyme liberating 1 mol product per min.…”

Section: Methodsmentioning

confidence: 99%

“…Real-time RT-PCR-Real-time PCR was performed as previously reported (13). Primer sequences are shown in supplemental Table S1.…”

Section: Methodsmentioning

confidence: 99%

The Plasma Membrane Sialidase NEU3 Regulates the Malignancy of Renal Carcinoma Cells by Controlling β1 Integrin Internalization and Recycling

Tringali

Lupo

Silvestri

et al. 2012

Journal of Biological Chemistry

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Background: NEU3 is involved in ganglioside surface metabolism and is up-regulated in renal carcinoma cells. Results: NEU3 regulates ␤1 integrin trafficking and the downstream FAK/AKT pathway, influencing drug resistance and invasive potential. Conclusion: NEU3 is a key regulator of renal cell carcinoma malignancy. Significance: NEU3 could be a new target for molecular therapies for renal carcinoma.

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RETRACTED ARTICLE: Silencing of membrane-associated sialidase Neu3 diminishes apoptosis resistance and triggers megakaryocytic differentiation of chronic myeloid leukemic cells K562 through the increase of ganglioside GM3

Cited by 48 publications

References 41 publications

SIRT1 is a critical regulator of K562 cell growth, survival, and differentiation

SIRT1 is a critical regulator of K562 cell growth, survival, and differentiation

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

The Plasma Membrane Sialidase NEU3 Regulates the Malignancy of Renal Carcinoma Cells by Controlling β1 Integrin Internalization and Recycling

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