Effects of the tyrosine kinase inhibitor imatinib mesylate on a Bcr-Abl-positive cell line: suppression of autonomous cell growth but no effect on decreased adhesive property and morphological changes.
Expression of the Bcr-Abl oncoprotein alters various aspects of hematopoietic cells. We investigated the effects of a Bcr-Abl tyrosine kinase inhibitor, imatinib mesylate, on the proliferation, adhesive properties, and morphology of a Bcr-Abl-transferred cell line, TF-1 Bcr-Abl, in comparison with parental TF-1. First, the factor-independent growth of TF-1 Bcr-Abl was inhibited in the presence of imatinib mesylate, but this inhibition was overcome by addition of exogenous granulocyte-macrophage colony-stimulating factor. Imatinib mesylate remarkably reduced tyrosine phosphorylation of Bcr-Abl, Cbl, and Crkl in a time-dependent manner, and their complex formation also was affected. Imatinib mesylate inhibited activation of Stat5 rather than the MEK-ERK1/2 pathway. TF-1 Bcr-Abl cells exhibited a round shape, unlike TF-1, and the adhesive property to fibronectin was much lower than that of TF-1. Although the Bcr-Abl oncoprotein may be involved negatively in cell adhesion, the decreased adhesion and altered morphology of TF-1 Bcr-Abl cells were minimally affected by imatinib mesylate and seemed independent of Bcr-Abl kinase activity. The present data indicated that the Bcr-Abl-specific kinase inhibitor cannot control Bcr-Abl-induced cell alterations other than autonomous growth.
Nishihara
Toshio
T
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Miura
Yasuo
Y
Tohyama
Yumi
Y
Mizutani
Chisato
C
Hishita
Terutoshi
T
Ichiyama
Satoshi
S
Uchiyama
Takashi
T
Tohyama
Kaoru
K
D001549:Benzamides; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D048429:Cell Size / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D000068877:Imatinib Mesylate; D007951:Leukemia, Myeloid / Q000473:pathology*; D008894:Milk Proteins; D050722:Oncogene Protein v-cbl; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050737:Proto-Oncogene Proteins c-crk; D011743:Pyrimidines / Q000494:pharmacology*; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors; D014162:Transfection
D001549:Benzamides; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D050722:Oncogene Protein v-cbl; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D011743:Pyrimidines; D015682:Retroviridae Proteins, Oncogenic; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl