Abstract
Nucleolin (C23) is an important anti-apoptotic protein that is ubiquitously expressed in exponentially growing eukaryotic cells. In order to understand the impact of C23 in radiation therapy, we attempted to investigate the relationship of C23 expression with the radiosensitivity of human non-small cell lung cancer (NSCLC) cells. We investigated the role of C23 in activating the catalytic subunit of DNA-dependent protein kinase (DNA- PKcs), which is a critical protein for DNA double-strand breaks (DSBs) repair. As a result, we found that the expression of C23 was negatively correlated with the radiosensitivity of NSCLC cell lines. In vitro clonogenic survival assays revealed that C23 knockdown increased the radiosensitivity of a human lung adenocarcinoma cell line, potentially through the promotion of radiation-induced apoptosis and adjusting the cell cycle to a more radiosensitive stage. Immunofluorescence data revealed an increasing quantity of γ-H2AX foci and decreasing radiation-induced DNA damage repair following knockdown of C23. To further clarify the mechanism of C23 in DNA DSBs repair, we detected the expression of DNA-PKcs and C23 proteins in NSCLC cell lines. C23 might participate in DNA DSBs repair for the reason that the expression of DNA-PKcs decreased at 30, 60, 120 and 360 minutes after irradiation in C23 knockdown cells. Especially, the activity of DNA-PKcs phosphorylation sites at the S2056 and T2609 was significantly suppressed. Therefore we concluded that C23 knockdown can inhibit DNA-PKcs phosphorylation activity at the S2056 and T2609 sites, thus reducing the radiation damage repair and increasing the radiosensitivity of NSCLC cells. Taken together, the inhibition of C23 expression was shown to increase the radiosensitivity of NSCLC cells, as implied by the relevance to the notably decreased DNA-PKcs phosphorylation activity at the S2056 and T2609 clusters. Further research on targeted C23 treatment may promote effectiveness of radiotherapy and provide new targets for NSCLC patients.
Highlights
Over the past twenty years, the worldwide incidence of non-small cell lung cancer (NSCLC) and associated mortality have increased steadily each year (Silvia et al, 2014)
We investigated the role of C23 in activating the catalytic subunit of DNA-dependent protein kinase (DNAPKcs), which is a critical protein for DNA double-strand breaks (DSBs) repair
We considered that the expression of C23 was negatively correlated with the radiosensitivity of NSCLC cell lines
Summary
Over the past twenty years, the worldwide incidence of non-small cell lung cancer (NSCLC) and associated mortality have increased steadily each year (Silvia et al, 2014). Significant advancements in the treatment of NSCLC, only minimal increases in survival rates have been produced (Fernandes et al, 2012). New treatment modalities that improve survival rates are urgently needed. A clearer understanding of the biology of NSCLC at a molecular level will aide materially in the development of these modalities, including ways to accurately predict the prognosis of patients with certain clinical-pathological characteristics and identification of new targets for radiation therapy. Improving tumor radiosensitivity is an effective way to increase the potency of radiation therapy. Tumor radiosensitivity is associated with a variety of factors, including cell apoptosis, radiation damage repair, and adjusting cell division cycle of cancer cells, etc
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