a 2010

Dasatinib suppresses MEK/ERK pathway activity without sustained BCR-ABL inhibition and promotes BIM dependent apoptosis in chronic myeloid leukaemia cells.

ŠIMARA, Pavel, Stanislav STEJSKAL, Martina PETERKOVÁ, Jiří MAYER, Zdeněk RÁČIL et. al.

Basic information

Original name

Dasatinib suppresses MEK/ERK pathway activity without sustained BCR-ABL inhibition and promotes BIM dependent apoptosis in chronic myeloid leukaemia cells.

Name in Czech

Dasatinib potlačuje aktivitu MEK/ERK signální dráhy bez kontinuální inhibice BCR-ABL a podporuje BIM-dependentní apoptózu u buněk chronické myeloidní leukemie.

Authors

ŠIMARA, Pavel (203 Czech Republic, guarantor), Stanislav STEJSKAL (203 Czech Republic), Martina PETERKOVÁ (203 Czech Republic), Jiří MAYER (203 Czech Republic), Zdeněk RÁČIL (203 Czech Republic), Irena KRONTORÁD KOUTNÁ (203 Czech Republic) and Michal KOZUBEK (203 Czech Republic)

Edition

XXIV. Olomoucké hematologické dny s mezinárodní účastí. 2010

Other information

Language

English

Type of outcome

Konferenční abstrakt

Field of Study

30200 3.2 Clinical medicine

Country of publisher

Czech Republic

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

RIV identification code

RIV/00216224:14330/10:00044247

Organization unit

Faculty of Informatics

ISSN

Keywords (in Czech)

dasatinib; CML

Keywords in English

dasatinib; CML
Změněno: 12/10/2010 09:17, prof. RNDr. Michal Kozubek, Ph.D.

Abstract

V originále

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.

Links

2B06052, research and development project
Name: Vytipování markerů, screening a časná diagnostika nádorových onemocnění pomocí vysoce automatizovaného zpracování multidimenzionálních biomedicínských obrazů (Acronym: Biomarker)
Investor: Ministry of Education, Youth and Sports of the CR, Determination of markers, screening and early diagnostics of cancer diseases using highly automated processing of multidimensional biomedical images