Persistent Activation of the Fyn/ERK Kinase Signaling Axis Mediates Imatinib Resistance in Chronic Myelogenous Leukemia Cells through Upregulation of Intracellular SPARC

Fenouille, Nina; Puissant, Alexandre; Dufies, Maeva; Robert, Guillaume; Jacquel, Arnaud; Ohanna, Mickaël; Deckert, Marcel; Pasquet, Jean‐Max; Mahon, François‐Xavier; Cassuto, Jill‐Patrice; Raynaud, Sophie; Tartare‐Deckert, Sophie; Auberger, Patrick

doi:10.1158/0008-5472.can-10-2034

Cited by 61 publications

(65 citation statements)

References 43 publications

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“…Depletion of SPARC promoted the nuclear accumulation of p53 and reduction in nuclear MDM2 levels, indicative of reduced phosphorylation and stability of MDM2. SPARC, being a secreted protein in A375 cells (Fenouille et al, 2010), was detected predominantly associated with the microsomal fraction (F2). Taken together, these results suggest that SPARC signaling downregulates p53 levels through the Akt/MDM2 pathway.…”

Section: Sparc Deficiency Reduces Clonogenicity and Promotes Time-depmentioning

confidence: 99%

SPARC functions as an anti-stress factor by inactivating p53 through Akt-mediated MDM2 phosphorylation to promote melanoma cell survival

et al. 2011

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Aberrant expression of Secreted Protein Acidic and Rich in Cysteine (SPARC)/osteonectin has been associated with an invasive tumor cell phenotype and poor outcome in human melanomas. Although it is known that SPARC controls melanoma tumorigenesis, the precise role of SPARC in melanoma cell survival is still unclear. Here, we show that SPARC has a cell-autonomous survival activity, which requires Akt-dependent regulation of p53. Suppression of SPARC by RNA interference in several human melanoma cells and xenografted A375 tumors triggers apoptotic cell death through the mitochondrial intrinsic pathway and activation of caspase-3. Cell death induced by depletion of SPARC is dependent on p53 and induction of Bax, and results in the generation of ROS. Stabilization of p53 in SPARC-depleted cells is associated with a decrease in Akt-mediated activating phosphorylation of MDM2. Inhibition of Akt signaling pathway is important for the observed changes as overexpression of constitutively active Akt protects cells against apoptosis induced by SPARC depletion. Conversely, increased expression of SPARC stimulates Akt and MDM2 phosphorylation, thus facilitating p53 degradation. Finally, we show that overexpression of SPARC renders cells more resistant to the p53-mediated cytotoxic effects of the DNA-damaging drug actinomycin-D. Our study indicates that SPARC functions through activation of Akt and MDM2 to limit p53 levels and that acquired expression of SPARC during melanoma development would confer survival advantages through suppression of p53-dependent apoptotic pathways.

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Section: Sparc Deficiency Reduces Clonogenicity and Promotes Time-depmentioning

confidence: 99%

SPARC functions as an anti-stress factor by inactivating p53 through Akt-mediated MDM2 phosphorylation to promote melanoma cell survival

et al. 2011

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“…SPARC was also found to be downregulated in acute myeloid leukemia (AML) with MLL rearrangements, usually associated with unfavorable prognosis, and upregulated in AML with t(8;21) or inv (16), which is usually associated with favorable prognosis, although no correlation of SPARC expression with outcome was reported (24). In chronic myelogenous leukemia, the accumulation of intracellular SPARC mediated by the Fyn/ERK signaling pathway seemingly contributed to imatinib resistance (25).…”

Section: Introductionmentioning

confidence: 99%

SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome

et al. 2014

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Aberrant expression of the secreted protein, acidic, cysteine-rich (osteonectin) (SPARC) gene, which encodes a matricellular protein that participates in normal tissue remodeling, is associated with a variety of diseases including cancer, but the contribution of SPARC to malignant growth remains controversial. We previously reported that SPARC was among the most upregulated genes in cytogenetically normal acute myeloid leukemia (CN-AML) patients with gene-expression profiles predictive of unfavorable outcome, such as mutations in isocitrate dehydrogenase 2 (IDH2-R172) and overexpression of the oncogenes brain and acute leukemia, cytoplasmic (BAALC) and v-ets erythroblastosis virus E26 oncogene homolog (ERG). In contrast, SPARC was downregulated in CN-AML patients harboring mutations in nucleophosmin (NPM1) that are associated with favorable prognosis. Based on these observations, we hypothesized that SPARC expression is clinically relevant in AML. Here, we found that SPARC overexpression is associated with adverse outcome in CN-AML patients and promotes aggressive leukemia growth in murine models of AML. In leukemia cells, SPARC expression was mediated by the SP1/NF-κB transactivation complex. Furthermore, secreted SPARC activated the integrinlinked kinase/AKT (ILK/AKT) pathway, likely via integrin interaction, and subsequent β-catenin signaling, which is involved in leukemia cell self-renewal. Pharmacologic inhibition of the SP1/NF-κB complex resulted in SPARC downregulation and leukemia growth inhibition. Together, our data indicate that evaluation of SPARC expression has prognosticative value and SPARC is a potential therapeutic target for AML.

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“…23 Conversely, SPARC overexpression characterizes CML cells displaying resistance to imatinib in vitro, suggesting a role in myeloid clone progression. 24 Herein, we investigated the role of SPARC in the BM stromal alterations associated with myeloproliferation. Altogether, our results suggest that stromal SPARC plays a key role in sustaining the detrimental fibrosis that occurs in myeloid malignancies and reveal SPARC's influence on the BM hematopoietic response in myeloproliferative conditions.…”

Section: Introductionmentioning

confidence: 99%

Stromal SPARC contributes to the detrimental fibrotic changes associated with myeloproliferation whereas its deficiency favors myeloid cell expansion

Tripodo

Sangaletti

Guarnotta

et al. 2012

Blood

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In myeloid malignancies, the neoplastic clone outgrows normal hematopoietic cells toward BM failure. This event is also sustained by detrimental stromal changes, such as BM fibrosis and osteosclerosis, whose occurrence is harbinger of a dismal prognosis. We show that the matricellular protein SPARC contributes to the BM stromal response to myeloproliferation. The degree of SPARC expression in BM stromal elements, including CD146 ؉ mesenchymal stromal cells, correlates with the degree of stromal changes, and the sever-

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Persistent Activation of the Fyn/ERK Kinase Signaling Axis Mediates Imatinib Resistance in Chronic Myelogenous Leukemia Cells through Upregulation of Intracellular SPARC

Cited by 61 publications

References 43 publications

SPARC functions as an anti-stress factor by inactivating p53 through Akt-mediated MDM2 phosphorylation to promote melanoma cell survival

SPARC functions as an anti-stress factor by inactivating p53 through Akt-mediated MDM2 phosphorylation to promote melanoma cell survival

SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome

Stromal SPARC contributes to the detrimental fibrotic changes associated with myeloproliferation whereas its deficiency favors myeloid cell expansion

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