Therapeutic implications of Src independent calcium mobilization in diffuse large B-cell lymphoma

Hollmann, Christiane; Tzankov, Alexandar; Martínez‐Marignac, Verónica L.; Baker, Kristi; Grygorczyk, Czeslawa; Grygorczyk, Ryszard; Foulkes, William D.; Nadeau, Jay L.; Dirnhofer, Stephan; Aloyz, Raquel

doi:10.1016/j.leukres.2009.08.030

Cited by 13 publications

(12 citation statements)

References 37 publications

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“…8 In B lymphoma cells, including a BL cell line, SRC inhibition, mediated by the multitargeted tyrosine kinase inhibitor dasatinib and the SRC inhibitors PP1 and PP2, induced a marked antiproliferative effect. [9][10][11] These observations suggest that SRC could represent an important therapeutic target for BL.…”

Section: Discussionmentioning

confidence: 90%

“…Interestingly, following SRC inhibition, we also found a decrease in the active form of AKT, It has been recently shown that alterations in the activity of the SRC family kinases could play a key role in B lymphoma survival and growth. [9][10][11] Inhibition of SRC, whose aberrant activation is implicated in the onset and progression of many human cancers, is among the most promising strategies for cancer therapy. 8 In B lymphoma cells, including a BL cell line, SRC inhibition, mediated by the multitargeted tyrosine kinase inhibitor dasatinib and the SRC inhibitors PP1 and PP2, induced a marked antiproliferative effect.…”

Section: Discussionmentioning

confidence: 99%

“…8 It has been recently shown that SRC family kinases are hyperactivated in many B lymphoma cell lines and primary lymphoma samples but not in normal B cells. [9][10][11] Moreover, SRC inhibition, mediated by the multitargeted tyrosine kinase inhibitor dasatinib and the SRC inhibitors PP1 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo [3,4-d]pyrimidine) and PP2, induced an antiproliferative effect on diffuse large B-cell lymphoma cell lines. [9][10][11] Although these studies are mostly focused on a different lymphoma type, one includes the BL cell line, BJAB and shows that both PP1 and PP2 have antiproliferative effects on this cell line.…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11] Moreover, SRC inhibition, mediated by the multitargeted tyrosine kinase inhibitor dasatinib and the SRC inhibitors PP1 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo [3,4-d]pyrimidine) and PP2, induced an antiproliferative effect on diffuse large B-cell lymphoma cell lines. [9][10][11] Although these studies are mostly focused on a different lymphoma type, one includes the BL cell line, BJAB and shows that both PP1 and PP2 have antiproliferative effects on this cell line. 10 Therefore, even if a study that extensively describes the effects of SRC inhibition in BL cells is lacking, this observation suggests that SRC could represent a therapeutic target also for BL.…”

Section: Introductionmentioning

confidence: 99%

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Antitumor activity of new pyrazolo[3,4-d]pyrimidine SRC kinase inhibitors in Burkitt lymphoma cell lines and its enhancement by WEE1 inhibition

et al. 2012

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Antitumor activity of new pyrazolo[3,4-d]pyrimidine SRC kinase inhibitors in Burkitt lymphoma cell lines and its enhancement by WEE1 inhibition

et al. 2012

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“…32 Moreover, SU-DHL-4 and OCI-LY-1 are reported to have a similar moderate activation of PLC γ 2. 33 This may indicate that cancer cells may suppress the downstream effects of chronic BCR signaling by either Bcl-2/IP 3 R interactions to inhibit IP 3 R signaling or alternatively by switching to the less sensitive IP 3 R3 isoform. From our immunoprecipitation experiments, it was evident that TAT-IDP S did not completely disrupt the binding of Bcl-2 to IP 3 Rs.…”

Section: Discussionmentioning

confidence: 99%

IP3R2 levels dictate the apoptotic sensitivity of diffuse large B-cell lymphoma cells to an IP3R-derived peptide targeting the BH4 domain of Bcl-2

et al. 2013

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Disrupting inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)/B-cell lymphoma 2 (Bcl-2) complexes using a cell-permeable peptide (stabilized TAT-fused IP3R-derived peptide (TAT-IDPS)) that selectively targets the BH4 domain of Bcl-2 but not that of B-cell lymphoma 2-extra large (Bcl-Xl) potentiated pro-apoptotic Ca2+ signaling in chronic lymphocytic leukemia cells. However, the molecular mechanisms rendering cancer cells but not normal cells particularly sensitive to disrupting IP3R/Bcl-2 complexes are poorly understood. Therefore, we studied the effect of TAT-IDPS in a more heterogeneous Bcl-2-dependent cancer model using a set of ‘primed to death' diffuse large B-cell lymphoma (DL-BCL) cell lines containing elevated Bcl-2 levels. We discovered a large heterogeneity in the apoptotic responses of these cells to TAT-IDPS with SU-DHL-4 being most sensitive and OCI-LY-1 being most resistant. This sensitivity strongly correlated with the ability of TAT-IDPS to promote IP3R-mediated Ca2+ release. Although total IP3R-expression levels were very similar among SU-DHL-4 and OCI-LY-1, we discovered that the IP3R2-protein level was the highest for SU-DHL-4 and the lowest for OCI-LY-1. Strikingly, TAT-IDPS-induced Ca2+ rise and apoptosis in the different DL-BCL cell lines strongly correlated with their IP3R2-protein level, but not with IP3R1-, IP3R3- or total IP3R-expression levels. Inhibiting or knocking down IP3R2 activity in SU-DHL-4-reduced TAT-IDPS-induced apoptosis, which is compatible with its ability to dissociate Bcl-2 from IP3R2 and to promote IP3-induced pro-apoptotic Ca2+ signaling. Thus, certain chronically activated B-cell lymphoma cells are addicted to high Bcl-2 levels for their survival not only to neutralize pro-apoptotic Bcl-2-family members but also to suppress IP3R hyperactivity. In particular, cancer cells expressing high levels of IP3R2 are addicted to IP3R/Bcl-2 complex formation and disruption of these complexes using peptide tools results in pro-apoptotic Ca2+ signaling and cell death.

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Src-family tyrosine kinases and the Ca2+ signal

Anguita

Villalobo

2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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In this review, we shall describe the rich crosstalk between non-receptor Src-family kinases (SFKs) and the Ca transient generated in activated cells by a variety of extracellular and intracellular stimuli, resulting in diverse signaling events. The exchange of information between SFKs and Ca is reciprocal, as it flows in both directions. These kinases are main actors in pathways leading to the generation of the Ca signal, and reciprocally, the Ca signal modulates SFKs activity and functions. We will cover how SFKs participate in the generation of the cytosolic Ca rise upon activation of a series of receptors and the mechanism of clearance of this Ca signal. The role of SFKs modulating Ca-translocating channels participating in these events will be amply discussed. Finally, the role of the Ca sensor protein calmodulin on the activity of c-Src, and potentially on other SFKs, will be outlined as well. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.

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Therapeutic implications of Src independent calcium mobilization in diffuse large B-cell lymphoma

Cited by 13 publications

References 37 publications

Antitumor activity of new pyrazolo[3,4-d]pyrimidine SRC kinase inhibitors in Burkitt lymphoma cell lines and its enhancement by WEE1 inhibition

Antitumor activity of new pyrazolo[3,4-d]pyrimidine SRC kinase inhibitors in Burkitt lymphoma cell lines and its enhancement by WEE1 inhibition

IP3R2 levels dictate the apoptotic sensitivity of diffuse large B-cell lymphoma cells to an IP3R-derived peptide targeting the BH4 domain of Bcl-2

Src-family tyrosine kinases and the Ca2+ signal

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