Abstract
Enhanced radiosensitivity at low doses of ionizing radiation (IR) (0.2 to 0.6 Gy) has been reported in several cell lines. This phenomenon, known as low doses hyper-radiosensitivity (LDHRS), appears as an opportunity to decrease toxicity of radiotherapy and to enhance the effects of chemotherapy. However, the effect of low single doses IR on cell death is subtle and the mechanism underlying LDHRS has not been clearly explained, limiting the utility of LDHRS for clinical applications. To understand the mechanisms responsible for cell death induced by low-dose IR, LDHRS was evaluated in DLD-1 human colorectal cancer cells and the expression of 80 microRNAs (miRNAs) was assessed by qPCR array. Our results show that DLD-1 cells display an early DNA damage response and apoptotic cell death when exposed to 0.6 Gy. miRNA expression profiling identified 3 over-expressed (miR-205-3p, miR-1 and miR-133b) and 2 down-regulated miRNAs (miR-122-5p, and miR-134-5p) upon exposure to 0.6 Gy. This miRNA profile differed from the one in cells exposed to high-dose IR (12 Gy), supporting a distinct low-dose radiation-induced cell death mechanism. Expression of a mimetic miR-205-3p, the most overexpressed miRNA in cells exposed to 0.6 Gy, induced apoptotic cell death and, more importantly, increased LDHRS in DLD-1 cells. Thus, we propose miR-205-3p as a potential radiosensitizer to low-dose IR.
Highlights
Radiotherapy (RT) is the standard treatment for most cancers, including colorectal cancer (CRC)
To understand the mechanisms responsible for cell death induced by low-dose ionizing radiation (IR), low doses hyperradiosensitivity (LDHRS) was evaluated in DLD-1 human colorectal cancer cells and the expression of 80 microRNAs was assessed by qPCR array
Our results show that DLD-1 cells display an early DNA damage response and apoptotic cell death when exposed to 0.6 Gy. miRNA expression profiling identified 3 over-expressed and 2 downregulated miRNAs upon exposure to 0.6 Gy
Summary
Radiotherapy (RT) is the standard treatment for most cancers, including colorectal cancer (CRC). Conventional RT protocols for a localized solid tumor include the administration of high-dose (60–70 Gy) ionizing radiation (IR), delivered in about 30 to 35 doses (2 Gy per day). These protocols are very effective, but are not free of toxicity and secondary side effects [3, 4,5,6,7]. The linear-quadratric (LQ) model has been widely used to predict the effects on cell survival after the exposure to IR. This model is generally used for calculating the effect of doses in a RT treatment. The curvilinear approach of LQ model show a correlation between cell death and IR at doses ≥ 2 Gy [1,2,3,4], assuming little or even no effect at lower doses (≤ 1 Gy) [8,9,10,11]
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