Oncotarget

Research Papers:

Combinatorial effects of an epigenetic inhibitor and ionizing radiation contribute to targeted elimination of pancreatic cancer stem cell

Hyun-Mi Kwon, Eun-Jin Kang, Keunsoo Kang, Sung-Dae Kim, Kwangmo Yang and Joo Mi Yi _

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Oncotarget. 2017; 8:89005-89020. https://doi.org/10.18632/oncotarget.21642

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Abstract

Hyun-Mi Kwon1,*, Eun-Jin Kang1,*, Keunsoo Kang2, Sung-Dae Kim1, Kwangmo Yang1 and Joo Mi Yi1

1Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan 46033, South Korea

2Department of Microbiology, Dankook Universty, Cheonan 31116, South Korea

*These authors have contributed equally to this work

Correspondence to:

Joo Mi Yi, email: jmyi@dirams.re.kr

Keywords: DNA methylation inhibitor, radiation, pancreatic cancer, cancer stem cell

Received: June 29, 2017     Accepted: August 27, 2017     Published: October 06, 2017

ABSTRACT

Pancreatic cancer is associated with a high mortality rate, owing to de novo and acquired drug resistance, thereby leading to highly invasive and metastatic pancreatic cancer cells. Therefore, targeting pancreatic cancer stem cells (CSCs) may be a novel therapeutic strategy for the treatment of pancreatic cancer. Here, we combined a DNA methylation inhibitor (5-aza-2’-deoxycytidine; 5-aza-dC) and ionizing radiation (IR) to improve anti-cancer effects by inhibiting growth and proliferation and promoting apoptosis of pancreatic cancer cells in vitro and in vivo. Importantly, the combinatorial effect of 5-aza-dC with IR on sphere-forming pancreatic cancer cells was preferentially targeted toward CSCs through the downregulation of regulatory factors of self-renewal and CSC surface markers. We next performed the RNA sequencing to understand the underlying cellular mechanisms of the combined treatment with IR and 5-aza-dC in pancreatic cancer cells. Global transcriptome profiling indicated that the expression of the Oct4-centered transcriptional network of genes was significantly downregulated in cells with combination treatment. Our data suggested that combination treatment with DNA methylation inhibitor and IR may be a novel therapeutic strategy for pancreatic cancer. Overall, these findings support the use of epigenetic therapy in combination with radiotherapy to improve therapeutic efficacy by targeting and eradicating pancreatic CSCs.


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