Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic lymphocytic leukemia (CLL) is a B-cell lymphoid neoplasm with deregulated apoptosis and overexpression of several antiapoptotic BCL-2 proteins. GX15-070/Obatoclax is a small-molecule BH3 mimetic compound that has shown activity against several hematologic malignancies and solid tumors. In the present work, we report that GX15-070 led to the disruption of BCL-2/BIM and MCL-1/BAK complexes in CLL cells, followed by the activation of the mitochondrial apoptotic pathway. CLL cells showed lower sensitivity to GX15-070 than primary mantle cell lymphoma (MCL) ones, in correlation with higher levels of phosphorylated BCL-2 at serine 70 residue (pBCL-2(Ser70)) in CLL cells. Decrease in BCL-2 phosphorylation by extracellular signal-regulated kinase (ERK)1/2 inhibition increased CLL sensitivity to GX15-070, while blocking BCL-2 dephosphorylation using a PP2A antagonist reduced the activity of this BH3 mimetic. GX15-070 activity was increased by cotreatment with the proteasome inhibitor bortezomib. However, as proteasome inhibition led to the accumulation of phosphorylated BCL-2, the degree of interaction between GX15-070 and bortezomib was regulated by basal pBCL-2(Ser70) levels. These results support the role of BCL-2 phosphorylation as a mechanism of resistance to BH3 mimetic compounds, and demonstrate that combination approaches including ERK inhibitors could enhance BH3 mimetics activity both alone or in combination with proteasome inhibitors.
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PMID:BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells. 1859 39

Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN or CD147), a member glycoprotein enriched on the surface of many malignant tumor cells, promotes tumor progression and confers resistance to some chemotherapeutic drugs. To investigate the possible role of CD147 in the macrophage-like lymphoid neoplasm P388D1 cells progression, we used RNA interference approach to silence CD147 expression. The results showed that silencing of CD147 in P388D1 cells impeded the expression of MMP11 at both mRNA and protein levels. The reduced CD147 expression also resulted in reductions in tumorigenicity, as well as decreased in regional lymph node metastasis. Furthermore, the down-regulation of CD147 expression sensitized cells to be more sensitive to chemotherapeutic drugs. Treatment of tumor cells with U-0126, an inhibitor of mitogen-activated protein kinase/Erk, also down-regulated the expression of MMP11. Our current results indicate that the expression of CD147 functionally mediates tumor progression and is a potential target for therapeutic anti-cancer drugs.
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PMID:Silencing CD147 inhibits tumor progression and increases chemosensitivity in murine lymphoid neoplasm P388D1 cells. 1912 48