Synergistic enhancement of NK cell-mediated cytotoxicity by combination of histone deacetylase inhibitor and ionizing radiation

Radiation Oncology

Jaeho Bae⁴  You-Soo Park³  Chi-Dae Kim²  Sae-Ock Oh⁵  Chi-Dug Kang⁶  Sun-Hee Kim⁴  Mi-Ju Kim⁴  Jiho Nam¹  Kwangmo Yang³  Jin-Hee Keum⁶  Cheol-Hun Son³ 

[1] Department of Radiation Oncology, Pusan National University Yangsan Hospital, Yangsan 626-770, South Korea;Department of Pharmacology, Pusan National University School of Medicine, Yangsan 626-870, South Korea;Medical Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan 619-953, South Korea;Medical Research Center for Ischemic Tissue regeneration, Pusan National University, Busan 609-735, South Korea;Department of Anatomy, Pusan National University School of Medicine, Yangsan 626-870, South Korea;Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, South Korea

关键词: Radioresistance;    Ionizing radiation;    HDAC inhibitors;    NKG2D ligands;   

Others  :  828917
DOI  :  10.1186/1748-717X-9-49

 received in 2013-07-20, accepted in 2013-12-06,  发布年份 2014

【 摘 要 】

Background

The overexpression of histone deacetylase (HDAC) and a subsequent decrease in the acetylation levels of nuclear histones are frequently observed in cancer cells. Generally it was accepted that the deacetylation of histones suppressed expression of the attached genes. Therefore, it has been suggested that HDAC might contribute to the survival of cancer cells by altering the NKG2D ligands transcripts. By the way, the translational regulation of NKG2D ligands remaines unclear in cancer cells. It appears the modulation of this unclear mechanism could enhance NKG2D ligand expressions and the susceptibility of cancer cells to NK cells. Previously, it was reported that irradiation can increase the surface expressions of NKG2D ligands on several cancer cell types without increasing the levels of NKG2D ligand transcripts via ataxia telangiectasia mutated and ataxia telangiectasia and Rad3 related (ATM-ATR) pathway, and suggested that radiation therapy might be used to increase the translation of NKG2D ligands.

Methods

Two NSCLC cell lines, that is, A549 and NCI-H23 cells, were used to investigate the combined effects of ionizing radiation and HDAC inhibitors on the expressions of five NKG2D ligands. The mRNA expressions of the NKG2D ligands were quantitated by multiplex reverse transcription-PCR. Surface protein expressions were measured by flow cytometry, and the susceptibilities of cancer cells to NK cells were assayed by time-resolved fluorometry using the DELFIA® EuTDA cytotoxicity kit and by flow cytometry.

Results

The expressions of NKG2D ligands were found to be regulated at the transcription and translation levels. Ionizing radiation and HDAC inhibitors in combination synergistically increased the expressions of NKG2D ligands. Furthermore, treatment with ATM-ATR inhibitors efficiently blocked the increased translations of NKG2D ligands induced by ionizing radiation but did not block the increased ligand translations induced by HDAC inhibitors. The study confirms that increased NKG2D ligand levels by ionizing radiation and HDAC inhibitors could synergistically enhance the susceptibilities of cancer cells to NK-92 cells.

Conclusions

This study suggests that the expressions of NKG2D ligands are regulated in a complex manner at the multilevel of gene expression, and that their expressions can be induced by combinatorial treatments in lung cancer cells.

【 授权许可】

   
2014 Son et al.; licensee BioMed Central Ltd.

【 图 表 】

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