Resveratrol inhibits the phosphatidylinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway in the human chronic myeloid leukemia K562 cell line.

Tao Sui,Li Ma,Xue Bai,Qing Li,Xinnv Xu

doi:10.3892/ol.2014.2014

Abstract

Resveratrol inhibits the initiation, promotion and progression of tumors, however, the mechanism by which resveratrol inhibits the proliferation of the human chronic myeloid leukemia K562 cell line remains unclear. The present study was conducted to investigate the effect of resveratrol on the activation of the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling cascade in K562 cells. Resveratrol showed significant cytotoxic effects and induced apoptosis in K562 cells in a dose- and time-dependent manner. In addition, resveratrol attenuated the phosphorylation of PI3K, Akt and mTOR in the K562 cells. Furthermore, the selected inhibitors of PI3K (LY294002), Akt (SH-6) and mTOR (rapamycin) enhanced the effects of resveratrol in K562 cells. In addition, cyclin D1 levels were found to decrease and the activation of caspase-3 was observed. Resveratrol was also found to significantly attenuate the phosphorylation of the downstream molecules, p70S6K and 4EBP1. These results suggested that the downregulation of the PI3K/Akt/mTOR signaling cascades may be a crucial mediator in the inhibition of proliferation and induction of apoptosis by resveratrol in K562 cells.

Highlights

Chronic myeloid leukemia (CML) is a clonal myeloproliferative hematopoietic stem cell disease, characterized by the presence of the Philadelphia chromosome, which is generated by the reciprocal translocation of the ABL1 oncogene localized on chromosome 9 with the breakpointKey words: phosphatidylinositide 3‐kinase, protein kinase B, mammalian target of rapamycin, chronic myeloid leukemia, resveratrol cluster region (BCR) on chromosome 22 [t [9; 22]] [1,2]
To further investigate whether resveratrol can induce the apoptosis of K562 cells, the cells were treated with 60 μM of resveratrol for 24 h and the apoptotic rate of the K562 cells was detected using Annexin V‐fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining (Fig. 1C and D)
To investigate whether phosphatidylinositide 3‐kinase (PI3K)/Akt phosphorylation is responsible for resveratrol‐induced inhibition of proliferation, the K562 cells were treated with various concentrations of resveratrol for 24 h

Summary

Introduction

Chronic myeloid leukemia (CML) is a clonal myeloproliferative hematopoietic stem cell disease, characterized by the presence of the Philadelphia chromosome, which is generated by the reciprocal translocation of the ABL1 oncogene localized on chromosome 9 with the breakpoint. The selective tyrosine kinase inhibitors (TKI), which target the ATP binding site of BCR/ABL, block BCR/ABL kinase activity and exhibit a positive therapeutic effect for CML [10,11]. TKIs, such as imatinib, are considered as a conventional treatment option for CML. CML patients may become relatively resistant to TKI therapy, including the second generation TKIs [12,13] and, the development of a therapeutic strategy that targets abnormal signaling cascades other than BCR/ABL is urgently required for CML treatment

Objectives

Methods

Results

Conclusion