Dasatinib suppresses MEK/ERK pathway activity without sustained BCR-ABL inhibition and promotes BIM dependent apoptosis in chronic myeloid leukaemia cells.
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| Year of publication | 2010 |
| Type | Conference abstract |
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| Description | Chronic myeloid leukaemia (CML) is a clonal disorder of haematopoietic stem cells, characterized by the BCR-ABL oncogene. The BCR-ABL oncogene encodes constitutively active tyrosin kinase. It was previously shown, that transient inhibition of BCR-ABL by dasatinib is sufficient to commit CML cells to apoptosis (Shah 2008). Dasatinib mediated apoptosis in K562 cell line is accompanied by increasing expression level of proapoptotic protein BIM. Our results confirmed high mRNA levels of BIM in both transiently and continuously treated (100nM dasatinib) K562 cells compared to low dose continuous (1nM) dasatinib treatment. Intracellular level of BIM protein is regulated via phosphorylation by ERK protein kinase and subsequent degradation in the proteasome. In our research, we inhibited proteasome degradation by bortezomib. Combination of dasatinib and bortezomib led to rapid increase in BIM expression after 20 minutes. However, we have not found any difference in cell viability caused by combinational treatment with bortezomib and dasatinib neither in continuous or in transient exposure. BIM degradation is enhanced by BCR-ABL downstream signalling pathway MEK-ERK, known to be extremely active in CML cells. Dasatinib blocks MEK-ERK pathway by BCR-ABL targeting. Surprisingly, our results reveal sustained inhibition of MEK-ERK pathway even in the case of re-activation of BCR-ABL after drug wash-out, leading to activation of proapoptotic BIM expression and inhibition of its degradation. These findings suggest that equal increase of BIM in the case of transient and continuous dasatinib treatment is caused by MEK-ERK inhibition. |
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