Abstract
Radioresistance has been an important factor in restricting efficacy of radiotherapy for non-small cell lung cancer (NSCLC) patients and new approaches to inhibit cancer growth and sensitize irradiation were warranted. Despite the important role of ubiquitin/proteasome system (UPS) during cancer progression and treatment, the expression and biological role of ubiquitin (Ub) in human NSCLC has not been characterized. In this study, we found that ubiquitin was significantly overexpressed in 75 NSCLC tissues, compared to their respective benign tissues by immunohistochemistry (P < 0.0001). Knock-down of ubiquitin by mixed shRNAs targeting its coding genes ubiquitin B (UBB) and ubiquitin C (UBC) suppressed the growth and increased the radiosensitivity in NSCLC H1299 cells. Apoptosis and γ H2AX foci induced by X-ray irradiation were enhanced by knock-down of ubiquitin. Western blot and immunostaining showed that knock-down of ubiquitin decreased the expression and translocation of NF-κB to the nucleus by reduced phospho-IκBα after irradiation. Suppression of ubiquitin decreased the proliferation and radioresistance of H1299 transplanted xenografts in nude mice by promoting apoptosis. Taken together, our results demonstrate the critical role of ubiquitin in NSCLC proliferation and radiosensitivity. Targeting ubiquitin may serve as a potentially important and novel approach for NSCLC prevention and therapy.
Highlights
Downregulation of ubiquitin inhibits the proliferation and radioresistance of non-small cell lung cancer cells in vitro and in vivo
To determine the role of ubiquitin in lung cancer development, we first investigated the expression of ubiquitin in 75 paired clinical non-small cell lung cancer (NSCLC) specimens
Among the 75 cases, positive ubiquitin expression was observed in 82.7% (62/75) of tumor tissues compared with 4.0% (3/75) of the paired adjacent non-tumor tissue (P, 0.0001, Fig. 1B and Table 1)
Summary
Downregulation of ubiquitin inhibits the proliferation and radioresistance of non-small cell lung cancer cells in vitro and in vivo. Correspondence and requests for materials should be addressed to Radioresistance has been an important factor in restricting efficacy of radiotherapy for non-small cell lung cancer (NSCLC) patients and new approaches to inhibit cancer growth and sensitize irradiation were warranted. Recent studies have shown that both monoubiquitin and polyubiquitin modifications have critical roles in the DNA damage response (DDR), including the direct controlling protein expression levels[18,19]. Nuclear factor-kB (NF-kB), an import transcriptional factor, is a typical intrinsic cellular suppressor of apoptosis After exposure to both low and high doses of ionizing radiation (IR), DNA damageinduced NF-kB promotes the expression of anti-apoptotic genes[20,21]. The activated NF-kB has been reported to be a novel regulator of tumor radioresistance, and targeting NF-kB-mediated pathway is likely to contribute to radiosensitizer development[20,21]
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