Entry #: 9
Date: 10 August 2017
Section: Radiation Biology Topic: Oleuropein and enhanced radiation sensitivity
Type: Original article

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OliveNetTM Journal Club

Expert review of literature related to olives and olive oil

D. Elizabeth McCord, Nancy B. Ray and Tom C. Karagiannis

Title

Oleuropein enhances radiation sensitivity of nasopharyngeal carcinoma by downregulating PDRG1 through HIF1a-repressed microRNA-519d

Author(s)

Xu T and Xiao D

Citation / Year

(1) / 2017

Keywords

Oleuropein, nasopharyngeal carcinoma, radiation sensitivity, hypoxia-inducible factor 1  (HIF1), p53 and DNA damage-regulated protein 1 (PDRG1), microRNA-519d

Summary

Radiotherapy is a frontline therapy for nasopharyngeal carcinoma and modulating radiation response with the use of a sensitiser is anticipated to enhance the therapeutic efficacy. In this study oleuropein, a key Olea-derived antioxidant was investigated for potential radiation sensitizing effects in cell culture and in vivo. Conventional clonogenic survival assays and tumor growth measurements using a nude mouse (Balb/c) human xenograft model were utilised. For the cell culture experiments cells were pre-treated with 200 μM oleuropein for 24 hours prior to irradiation (up to 10 Gy). In the in vivo model, tumor xenografts (106 cells in 100 μL) were allowed to establish for seven days. Oleuropein (1%) was added to the drinking water at day seven until the end of the experiment (day 21). Tumors were irradiated at days seven and 14 and tumor volumes were measured at days seven, 14 and 21. The findings indicated that oleuropein sensitized the nasopharyngeal carcinoma cell lines to the effects of radiation with significant reductions in colony formation compared to controls. Similarly, a significant reduction in tumor volume was observed in mice administered 1% oleuropein in the drinking compared to controls. The aim was then to determine a potential molecular mechanism accounting for the radiation sensitizing effects of oleuropein. Previous findings indicating that oleuropein decreases the protein expression of hypoxia-inducible factor 1 a (HIF1a) provided an important starting point (2). Similarly, findings indicating that modulation of the expression of miRNA has an effect on radiation sensitivity were considered in the overall hypothesis (3, 4).

Key points and implications

Using qRT-PCR and microarray technologies it was found that incubation of nasopharyngeal cell lines with 200 μM oleuropein for 24 hours, alters the expression of genes and miRNA. Both, hypoxia-inducible factor 1 a (HIF1a) and p53 and DNA damage-regulated protein 1 (PDRG1) were downregulated by oleuropein and the expression of 22 miRNA was upregulated. Using in silico analysis (miRanda algorithm), it was identified that PDRG1 contained a binding sequence for miR-519d (one of the 22 miRNA upregulated by oleuropein). Using conventional molecular biological techniques evidence suggested that the HIF1a-miR-519d-PDRG1 pathway is modulated by oleuropein resulting in the radiation sensitizing effects. The authors provide a working model for the radiation sensitizing effects of oleuropein which involves: decreased expression of HIF1a which in turn, represses expression of miR-519d which directly targets the PDRG1 RNA resulting in decreased protein expression. Note that overexpression of PRDG1 inhibits the radiation sensitizing effects by regulating the key DNA damage ataxia telangiectasia mutated (ATM)-p53 signalling pathway (5). Overall, oleuropein has been shown to have promising anti-cancer effects in experimental model systems, and radiation sensitization represents an additional potential beneficial effect of this compound.

Related publications

  1. T. Xu, D. Xiao, Oleuropein enhances radiation sensitivity of nasopharyngeal carcinoma by downregulating PDRG1 through HIF1alpha-repressed microRNA-519d. J Exp Clin Cancer Res 36, 3 (2017).
  2. A. Cardeno, M. Sanchez-Hidalgo, M. A. Rosillo, C. Alarcon de la Lastra, Oleuropein, a secoiridoid derived from olive tree, inhibits the proliferation of human colorectal cancer cell through downregulation of HIF-1alpha. Nutr Cancer 65, 147-156 (2013).
  3. C. Metheetrairut, F. J. Slack, MicroRNAs in the ionizing radiation response and in radiotherapy. Curr Opin Genet Dev 23, 12-19 (2013).
  4. A. Kraemer et al., MicroRNA-mediated processes are essential for the cellular radiation response. Radiat Res 176, 575-586 (2011).
  5. Z. Tao et al., The PDRG1 is an oncogene in lung cancer cells, promoting radioresistance via the ATM-P53 signaling pathway. Biomed Pharmacother 83, 1471-1477 (2016).