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

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.

Základní údaje

Originální název

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

Název česky

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

Autoři

ŠIMARA, Pavel (203 Česká republika, garant), Stanislav STEJSKAL (203 Česká republika), Martina PETERKOVÁ (203 Česká republika), Jiří MAYER (203 Česká republika), Zdeněk RÁČIL (203 Česká republika), Irena KRONTORÁD KOUTNÁ (203 Česká republika) a Michal KOZUBEK (203 Česká republika)

Vydání

XXIV. Olomoucké hematologické dny s mezinárodní účastí. 2010

Další údaje

Jazyk

angličtina

Typ výsledku

Konferenční abstrakt

Obor

30200 3.2 Clinical medicine

Stát vydavatele

Česká republika

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Kód RIV

RIV/00216224:14330/10:00044247

Organizační jednotka

Fakulta informatiky

ISSN

Klíčová slova česky

dasatinib; CML

Klíčová slova anglicky

dasatinib; CML

Změněno: 12. 10. 2010 09:17, prof. RNDr. Michal Kozubek, Ph.D.

Anotace

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.

Návaznosti

2B06052, projekt VaV

Název: Vytipování markerů, screening a časná diagnostika nádorových onemocnění pomocí vysoce automatizovaného zpracování multidimenzionálních biomedicínských obrazů (Akronym: Biomarker)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Vytipování markerů, screening a časná diagnostika nádorových onemocnění pomocí vysoce automatizovaného zpracování multidimenzionálních biomedicínských obrazů

Citovat

ŠIMARA, Pavel, Stanislav STEJSKAL, Martina PETERKOVÁ, Jiří MAYER, Zdeněk RÁČIL, Irena KRONTORÁD KOUTNÁ a Michal KOZUBEK. Dasatinib suppresses MEK/ERK pathway activity without sustained BCR-ABL inhibition and promotes BIM dependent apoptosis in chronic myeloid leukaemia cells. In XXIV. Olomoucké hematologické dny s mezinárodní účastí. 2010. ISSN 1213-5763.

@proceedings{889818,
   author = {Šimara, Pavel and Stejskal, Stanislav and Peterková, Martina and Mayer, Jiří and Ráčil, Zdeněk and Krontorád Koutná, Irena and Kozubek, Michal},
   booktitle = {XXIV. Olomoucké hematologické dny s mezinárodní účastí.},
   keywords = {dasatinib; CML},
   language = {eng},
   title = {Dasatinib suppresses MEK/ERK pathway activity without sustained BCR-ABL inhibition and promotes BIM dependent apoptosis in chronic myeloid leukaemia cells.},
   url = {http://www.olhemdny.cz/},
   year = {2010}
}

TY  - CONF
ID  - 889818
AU  - Šimara, Pavel - Stejskal, Stanislav - Peterková, Martina - Mayer, Jiří - Ráčil, Zdeněk - Krontorád Koutná, Irena - Kozubek, Michal
PY  - 2010
TI  - Dasatinib suppresses MEK/ERK pathway activity without sustained BCR-ABL inhibition and promotes BIM dependent apoptosis in chronic myeloid leukaemia cells.
KW  - dasatinib
KW  - CML
UR  - http://www.olhemdny.cz/
N2  - 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.
ER  -

ŠIMARA, Pavel, Stanislav STEJSKAL, Martina PETERKOVÁ, Jiří MAYER, Zdeněk RÁČIL, Irena KRONTORÁD KOUTNÁ a Michal KOZUBEK. Dasatinib suppresses MEK/ERK pathway activity without sustained BCR-ABL inhibition and promotes BIM dependent apoptosis in chronic myeloid leukaemia cells. In \textit{XXIV. Olomoucké hematologické dny s mezinárodní účastí.}. 2010. ISSN~1213-5763.

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