Constitutive activation of the MAPkinase p38 is critical for MMP-9 production and survival of B-CLL cells on bone marrow stromal cells

Ringshausen, Ingo; Dechow, Tobias; Schneller, Folker; Weick, K; Oelsner, Madlen; Peschel, Christian; Decker, Thomas

doi:10.1038/sj.leu.2403544

Cited by 62 publications

(56 citation statements)

References 38 publications

(35 reference statements)

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“…Our observations strengthen the notion that p38, a known regulator of stress responses, also regulates directed migration (32). Interestingly, p38 MAPK has been shown to be constitutively active in CLL, where it regulates MMP-9 production, suggesting a role in invasion (34). We report here that p38 activation is further increased upon CLL19 exposure in CIP4-depleted CLL cells, suggesting that control of its activation is important in regulating migration.…”

Section: Discussionsupporting

confidence: 76%

CIP4 Controls CCL19-Driven Cell Steering and Chemotaxis in Chronic Lymphocytic Leukemia

et al. 2013

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Solid tumor dissemination relies on the reprogramming of molecular pathways controlling chemotaxis. Whether the motility of nonsolid tumors such as leukemia depends on the deregulated expression of molecules decoding chemotactic signals remains an open question. We identify here the membrane remodeling F-BAR adapter protein Cdc42-interacting protein 4 (CIP4) as a key regulator of chemotaxis in chronic lymphocytic leukemia (CLL). CIP4 is expressed at abnormally high levels in CLL cells, where it is required for CCL19-induced chemotaxis. Upon CCL19 stimulation of CLL cells, CIP4 associates with GTP-bound Cdc42 and is recruited to the rear of the lamellipodium and along microspikes radiating through the lamellipodium. Consistent with its cellular distribution, CIP4 removal impairs both the assembly of the polarized lamellipodium and directional migration along a diffusible CCL19 gradient. Furthermore, CIP4 depletion results in decreased activation of WASP, but increased activation of PAK1 and p38 mitogen-activated protein kinase (MAPK). Notably, p38 MAPK inhibition results in impaired lamellipodium assembly and loss of directional migration. This suggests that CIP4 modulates both the WASP and p38 MAPK pathways to promote lamellipodium assembly and chemotaxis. Overall, our study reveals a critical role of CIP4 in mediating chemotaxis of CLL cells by controlling the dynamics of microspikecontaining protrusions and cell steering. Cancer Res; 73(11); 3412-24. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 76%

CIP4 Controls CCL19-Driven Cell Steering and Chemotaxis in Chronic Lymphocytic Leukemia

et al. 2013

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“…24 Our results confirmed the previously published data demonstrating that p38 MAPK is constitutively active and exerts a protective role in CLL. 32 We cannot totally exclude that IL-24 works also through a p38MAPK-independent mechanism; however, our data suggested a competition between IL-24 and SB 203580 for p38 MAPK activation as evidenced by sequential incubations. Indeed, IL-24 augmented p38 MAPK phosphorylation when added several hours after SB 203580, suggesting that the inhibitory effect of this drug is reversible (data not shown).…”

Section: Discussionmentioning

confidence: 41%

High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia

et al. 2006

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Chronic lymphocytic leukemia (CLL)-B-cells are quiescent differentiated cells that produce interleukin (IL)-10 and accumulate due to resistance to apoptosis. The mechanisms underlying such resistance are poorly understood. Herein we show that all CLL B-cells tested (30/30) display high mRNA and protein expression of the tumor suppressor Mda-7/IL-24, an IL-10 family member, in comparison to normal B cells. A downstream Mda-7 signaling target, p38 mitogen-activated protein kinase (MAPK) was highly phosphorylated in all CLL cells but not in normal B-cells. Mda-7 expression and p38 MAPK phosphorylation diminished in culture and the latter could be reinduced by recombinant (r)-IL-24 or LPS and Mda-7 transfection. Mda-7/IL-24 siRNA specifically inhibited p38 MAPK phosphorylation in CLL without affecting p38 MAPK, bcl2, or Lyn expression, further demonstrating the direct role of Mda-7/ IL-24 in p38 MAPK activation. Both pharmacological inhibition of p38 MAPK and Mda-7 silencing augmented spontaneous apoptosis by three-fold in CLL cells cultured in autologous serum, which was reversed by LPS and r-IL-24. We established the role of p38 MAPK in CLL cell survival and demonstrated a paradoxical effect, whereby Mda-7 and IL-24, inducers of apoptosis in diverse cancer cells, promote the survival of CLL B-cells through p38 MAPK activation.

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“…Recently, it was reported that the constitutive expression of MMP-9 in B-CLL cells depends on p38 MAP kinase activity, and that the survival of B-CLL cells on stroma is impaired upon inhibition of p38 or MMP-9 activity. 34 This indicates that MMP-9, in addition to its effect on angiogenesis, contributes to the well-known survival of leukemic cells in a bone marrow stroma microenvironment. Therefore, the blockade of MMP-9 production could also antagonize the antiapoptotic effect of stromal cells in vivo in B-CLL patients.…”

Section: Discussionmentioning

confidence: 99%

Hyperforin inhibits MMP-9 secretion by B-CLL cells and microtubule formation by endothelial cells

et al. 2006

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We previously reported that hyperforin (HF), a natural phloroglucinol purified from Saint John's wort, can induce the apoptosis of leukemic cells from patients with B-cell lymphocytic leukemia (B-CLL) ex vivo. We show here that treatment of cultured B-CLL patients' cells with HF results in a marked inhibition of their capacity to secrete matrix metalloproteinase-9, an essential component in neo-angiogenesis through degradation of the extracellular matrix process. The phloroglucinol acts by decreasing the production of the latent 92 kDa pro-enzyme. The inhibitory effect of HF is associated with a decrease in VEGF release by the leukemic cells. Moreover, HF is found to prevent the formation of microtubules by human bone marrow endothelial cells cultured on Matrigel, evidencing its capacity to inhibit vessel formation. Our results show the antiangiogenesis activity of HF and strengthen its potential interest in the therapy of B-CLL.

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Constitutive activation of the MAPkinase p38 is critical for MMP-9 production and survival of B-CLL cells on bone marrow stromal cells

Cited by 62 publications

References 38 publications

CIP4 Controls CCL19-Driven Cell Steering and Chemotaxis in Chronic Lymphocytic Leukemia

CIP4 Controls CCL19-Driven Cell Steering and Chemotaxis in Chronic Lymphocytic Leukemia

High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia

Hyperforin inhibits MMP-9 secretion by B-CLL cells and microtubule formation by endothelial cells

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