Nimotuzumab suppresses epithelial–mesenchymal transition and enhances apoptosis in low-dose UV-C treated salivary adenoid cystic carcinoma cell lines in vitro

Abstract

Salivary adenoid cystic carcinoma (SACC), which is one of the most common malignant tumors of the salivary glands, is associated with a poor long-term outcome. There are currently few therapeutic options for patients with SACC. Recent studies have shown the potential of the application of ultraviolet-C (UV-C) irradiation for the treatment of human cancer. In the present study, we investigated the effects of UV-C in the SACC cell lines SACC-83 and SACC-LM. High-dose UV-C (200 J/m) induced apoptosis and inhibited colony formation significantly. However, low-dose UV-C (10 J/m), which had little effect on apoptosis and colony formation, increased the ability of migration in SACC cells accompanied by a decrease in E-cadherin and an increase in vimentin, suggesting the occurrence of epithelial-mesenchymal transition (EMT). Low-dose UV-C (10 J/m) also resulted in upregulation of the phosphorylated forms of epidermal growth factor receptor (EGFR) and Akt (p-EGFR and p-Akt, respectively). Pretreatment with Nimotuzumab, an anti-EGFR monoclonal antibody, reversed the EMT as well as upregulation of p-EGFR/p-Akt induced by UV-C. Moreover, Nimotuzumab enhanced UV-C induced apoptosis and inhibition of colony formation. Our results indicate that EMT exerts a protective effect against apoptosis induced by low-dose UV-C. Thus, the combined application of Nimotuzumab and low-dose UV-C in vitro has an advantageous antitumor effect in SACC compared with the application of UV-C alone.

Effects of titanium dioxide nanoparticles on human keratinocytes

“…It must be pointed out that UV-C rays are significantly weaker than the ozone-penetrating UV-A and UV-B rays humans are exposed to daily. Despite UV-C rays being weaker rays that emit less irradiation; there are several publications that utilize these rays in studies that result in significant ROS accumulation and apoptosis (Dunkern et al, 2001; Jiang et al, 2014). Future experimental analysis utilizing UV-A and UV-B radiation may unearth an additive effect with TiO 2 that enhances apoptosis or cell proliferation toward a malignant phenotype.…”

Nimotuzumab inhibits epithelial–mesenchymal transition in prostate cancer by targeting the Akt/YB‐1/AR axis

“…Here, we showed that targeting EGF signaling with nimotuzumab significantly inhibited EMT of LNCaP cells. Consistently, Odero‐Marah et al reported that EGF plus transforming growth factor‐β1 (TGF‐β1) treatment induced EMT in LNCaP cells ; Jiang et al showed that nimotuzumab inhibited EMT in salivary adenoid cystic carcinoma cell lines ; Padthaisong et al showed that nimotuzumab targeted the metastasis of cholangiocarcinoma cells by suppressing EMT . Therefore, the effect of EGF on AR + cells might be specific for EMT, but not for cell growth.…”

“…Next, we turned to YB‐1, the transcriptional controller for AR , and its upstream signaling activator Akt , since Akt is an intracellular kinase responsive to nimotuzumab . Following nimotuzumab treatment, activated Akt (p‐Akt), activated YB‐1 (p‐YB‐1), and AR levels were all reduced, supporting their involvement in nimotuzumab‐mediated phenotypes.…”

“…The mechanisms by which nimotuzumab targets EMT are not completely understood. Jiang et al showed that, when challenged with low‐dose irradiation, EGFR and Akt were activated, enhancing EMT and protecting salivary adenoid cystic carcinoma cells from apoptosis; pretreatment with nimotuzumab inactivated both EGFR and Akt, reversed EMT, induced apoptosis, and thus improved the anti‐cancer effects of low‐dose irradiation . Huang et al showed that nimotuzumab could antagonize EGF‐induced Erk activation or the upregulation of matrix metalloproteinase 9 and snail (a transcription factor critical for TGFβ‐induced EMT), and reduced the invasiveness of adenoid cystic carcinoma cells .…”

“…Yet few studies have comprehensively examined the therapeutic efficacy of nimotuzumab in PC. Mechanistically, studies showed that by blocking Akt phosphorylation/activation, nimotuzumab enhanced radiosensitivity in breast cancer and lung cancer cells and suppressed EMT in cholangiocarcinoma and salivary adenoid carcinoma cells . However, it is not known whether the anti‐EMT effect of nimotuzumab was carried out by acting on the Akt/YB‐1/AR axis.…”