Combination therapy using TGF-β1 and STI-571 can induce apoptosis in BCR-ABL oncogene-expressing cells

Author:

Bakhshayesh Masoome1,Gohari Ladan Hosseini2,Barati Mahmood3,Safa Majid4

Affiliation:

1. Genetics department, School of Medicine , Iran University of Medical Sciences , Tehran , Iran ; Cellular & Molecular Research Center , Iran University of Medical Sciences , Tehran , Iran

2. Cellular & Molecular Research Center, Medical Laboratory Science Department, School of Allied Medicine , Iran University of Medical Sciences , Tehran , Iran

3. Department of Medical Biotechnology, Faculty of Allied Medicine , Iran University of Medical Sciences , Tehran , Iran

4. Cellular & Molecular Research Center , Iran University of Medical Sciences , Tehran , Iran

Abstract

Abstract The BCR-ABL oncogene is a tyrosine kinase gene that is over-expressed in CML. It inhibits the TGF-β1 signaling pathway. Due to resistance of cells to the tyrosine kinase inhibitor, STI-571, the combined effect of STI-571 and TGF-β1 on K562 cells was studied in the present research. Results revealed that the TGF-β1 cell signaling pathway, which is activated in K562 cells treated with TGF-β1, activates collective cell signaling pathways involved in survival and apoptosis. It is noteworthy that treating K562 cells with STI-571 triggered apoptotic pathways, accompanied by a reduction in proteins such as Bcl-xL, Bcl-2, p-AKT, p-Stat5, p-FOXO3, and Mcl-1 and an increase in the pro-apoptotic proteins PARP cleavage, and p27, leading to an increase in sub-G1 phase-arrested and Annexin-positive cells. Interestingly, the proliferation behavior of TGF-β1-induced cells was changed with the combination therapy, and STI-571-induced apoptosis was also prompted by this combination. Thus, combination treatment appears to promote sub-G1 cell cycle arrest compared to individually treated cells. Furthermore, it strongly triggered apoptotic signaling. In conclusion, TGF-β1 did not negatively impact the effect of STI-571, based on positive annexin cells, and AKT protein phosphorylation remains effective in apoptosis.

Publisher

Walter de Gruyter GmbH

Subject

Cellular and Molecular Neuroscience,General Biochemistry, Genetics and Molecular Biology,General Medicine

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