[Molecular mechanism of hydroxyurea enhances K562 cell apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand].

Abstract

OBJECTIVE:

To explore the molecular mechanism via which the chemotherapeutic drug hydroxyurea (HU) enhances K562 cell apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).

METHODS:

Chronic myelogenous leukemia-derived K562 and SVT-35 cells were treated with recombinant soluble TRAIL (rsTRAIL) alone or combined with HU for a time course, and the cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-4-sulfophenyl-2H-tetrazolium-phenazine methosulphate assay. Western blot was performed to analyze the activation of apoptosis-related protein kinases and the expression of apoptosis inhibitor molecules.

RESULTS:

The survival rates of SVT-35 and K562 cells treated with 1 μg/ml rsTRAIL for 24 hours were 32% and 93%, respectively. HU significantly increased the sensitivity of K562 cells to rsTRAIL cytotoxicity. Combination of rsTRAIL and HU resulted in the phosphorylation of rat sarcoma (RAS), mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase and in the significant reduction of apoptosis-inhibited molecule Fas associated death domain protein-like interleukin-1 beta-convening enzyme inhibitory protein and cellular inhibitor of apoptosis protein-1 in K562 cells.

CONCLUSIONS:

HU enhanced K562 cell sensitivity to rsTRAIL is mediated by Ras-MEK-ERK signaling pathway. Expression of antiapoptotic proteins cellular Fas associated death domain protein-like interleukin-1 beta-convening enzyme inhibitory protein and cellular inhibitor of apoptosis protein-1 is also down-regulated during this process. These results may through light on the therapeutic study of human chronic myelogenous leukemia.

• Authors: Yao-min Wu, Ya-xi Zhang, Juan Shi, Shi-lian Liu, Yan-xin Liu, De-xian Zheng
• Journal: Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae (Zhongguo Yi Xue Ke Xue Yuan Xue Bao) Vol. 34 Issue 2 Pg. 146-52 (Apr 2012) ISSN: 1000-503X [Print] China
• PMID: 22776600 (Publication Type: English Abstract, Journal Article)

Chemical References

• CASP8 and FADD-Like Apoptosis Regulating Protein
• Inhibitor of Apoptosis Proteins
• TNF-Related Apoptosis-Inducing Ligand
• Hydroxyurea

Topics

• Apoptosis (drug effects, physiology)
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Humans
• Hydroxyurea (pharmacology)
• Inhibitor of Apoptosis Proteins (metabolism)
• K562 Cells
• MAP Kinase Signaling System
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)