Increasing evidences suggests that various cancer types contain a population of cells that display stem cell properties. These cells are called cancer stem cells (CSCs). They are virtually resistant to radiation, and may contribute to treatment resistance and recurrence. Therefore, therapies specifically targeting CSCs will likely be needed for complete tumor eradication. Exposure of cells to ionizing radiation (IR) induces, not only, activation of multiple signaling pathways that play critical roles in cell fate determination, but also alteration of molecular pathways involved in cell death or survival. Recently, DNA methylation has been established as a critical epigenetic process involved in the regulation of gene expression in cancer cells, suggesting that DNA methylation inhibition may be an effective cancer treatment strategy. We therefore investigated the combination effect of a DNA methyltransferase inhibitor, 5-aza-2’-deoxycytidine (5-aza-dC), and radiation treatment in pancreatic cancer. Pancreatic cancer cell lines were initially tested for radiation sensitivity by ionizing radiation (IR) in vitro and were treated with 5-aza-dC. The effects of 5-aza-dC along with irradiation on cell growth, cell cycle distribution, apoptosis, and apoptosis-related gene expression were examined. Combination irradiation treatment with 5-aza-dC significantly decreased growth activity compared with irradiation or 5-aza-dC treatment alone. To understand whether combination treatment can target to pancreatic cancer stem cells, we observed that combination treatment can significantly reduce Oct4, Nanog, Sox2, CD133, and CD44 levels which are key factors for self-renewal pathway or cancer stem cell surface markers in pancreatic cancer cells, respectively. Using transcriptome analysis, OCT4 target genes showed differential expression pattern between irradiation or 5-aza-dC treatment alone and combination treatment. In addition, sphere forming assay supports these data in vitro and in vivo, describing that combination effect of IR and 5-aza-dC can reduce significantly sphere forming ability and proportion of side population (putative CSCs) significantly decreased in combination treated cells compared to control or single treatment. Therefore combined treatment of IR and 5-aza-dC is capable of eliminating pancreatic CSCs. Further investigation of this useful approach may lead to the development of a novel intervention for the cancer therapeutic strategy.
Citation Format: Joo Mi Yi, Hyun-Mi Kwon, Eun-Jin Kang, Kwangmo Yang. Combined treatment with radiation and epigenetic regulation improve to targeting cancer stem cells in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-227. doi:10.1158/1538-7445.AM2017-LB-227