Head and neck squamous cell carcinoma (HNSCC) is an important endemic disease in Taiwan with aggressive course and dismal outcome. Dasatinib is a Bcr-bl and Src kinase inhibitor that has potential against HNSCC. We recently disclosed that EGFR degradation is critical for dasatinib-induced apoptosis. Here, we further demonstrate that AMPK-dependent ER stress is responsible for this event. Dasatinib induced ER stress which mediated EGFR degradation in a c-cbl-dependent manner. AMPK activation induced by dasatinib might be due to ATP decrease through the up-regulation of pyruvate dehydrogenase kinase 4 (PDK4). Furthermore, activation of AMPK by metformin sensitized dasatinib-induced in vitro and in vivo anti-cancer effect. The correlation of AMPK activation and EGFR expression was seen in HNSCC cells and human tumor specimens. Our results disclose that AMPK-dependent ER stress plays a crucial role in the anti-cancer effect of dasatinib in HNSCC and further activation of AMPK by metformin might enhance dasatinib efficacy.
Epidermal growth factor receptor (EGFR) is an important oncoprotein that promotes cell growth and proliferation. Dasatinib, a bcr-abl inhibitor, has been approved clinically for the treatment of chronic myeloid leukemia and demonstrated to be effective against solid tumors in vitro through Src inhibition. Here, we disclose that EGFR degradation mediated dasatinib-induced apoptosis in head and neck squamous cell carcinoma (HNSCC) cells. HNSCC cells, including Ca9-22, FaDu, HSC3, SAS, SCC-25, and UMSCC1, were treated with dasatinib, and cell viability, apoptosis, and underlying signal transduction were evaluated. Dasatinib exhibited differential sensitivities against HNSCC cells. Growth inhibition and apoptosis were correlated with its inhibition on Akt, Erk, and Bcl-2, irrespective of Src inhibition. Accordingly, we found that down-regulation of EGFR was a determinant of dasatinib sensitivity. Lysosome inhibitor reversed dasatinib-induced EGFR down-regulation, and c-cbl activity was increased by dasatinib, indicating that dasatinib-induced EGFR down-regulation might be through c-cbl-mediated lysosome degradation. Increased EGFR activation by ligand administration rescued cells from dasatinib-induced apoptosis, whereas inhibition of EGFR enhanced its apoptotic effect. Estrogen receptor α (ERα) was demonstrated to play a role in Bcl-2 expression, and dasatinib inhibited ERα at the pretranslational level. ERα was associated with EGFR in dasatinib-treated HNSCC cells. Furthermore, the xenograft model showed that dasatinib inhibited HSC3 tumor growth through in vivo down-regulation of EGFR and ERα. In conclusion, degradation of EGFR is a novel mechanism responsible for dasatinib-induced apoptosis in HNSCC cells.
Head and neck squamous cell carcinoma (HNSCC) is a worldwide disease with aggressive course and dismal outcome. Dasatinib, a Bcr-abl and Src in hibitor, has been approved clinically for CML and shown activities against solid tumors in vitro. In our recent work, degradation of epidermal growth factor receptor (EGFR) plays a role in dasatinib-induced apoptosis in HNSCC cells. We further explored the mechanism of this event. ER stress was induced by dasatinib and played a role in dasatinib-EGFR degradation. C-cbl activation was induced by ER stress and shown to mediate ER-stress induced EGFR degradation. In addition, AMPK activation was induced by dasatinib, which was proved to be involved in dasatinib-induced ER stress and EGFR degradation. Activation of AMPK with metformin not only enhanced dasatinib-induced growth inhibition and apoptosis but also sensitized dasatinib-resistant cells. Furthermore, xenograft model showed that metformin potentiated anti-cancer effect of dasatinib through activation of AMPK and ER stress. Our results disclose that AMPK-dependent ER stress plays a crucial role in the anti-cancer effect of dasatinib in HNSCC and further activation of AMPK by metformin might enhance dasatinib efficacy. Citation Format: Yu-Chin Lin Lin, Meng-Hsuan Wu, Tzu-Tang Wei, Yun-Chieh Lin, Ching-Chow Chen. AMPK activation mediates dasatinib-induced EGFR degradation and apoptosis in head and neck cancer. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A73. doi:10.1158/1538-7445.CHTME14-A73
Introduction: Head and neck squamous cell carcinoma (HNSCC) is a worldwide prevalent cancer with aggressive clinical courses and dismal outcomes. Incorporation of cetuximab, an antibody against epidermal growth factor receptor, had led to advance of treatment, but showed a modest efficacy. Therefore, new treatment for HNSCC is needed. Dasatinib, a Bcr-Abl and Src inhibitor, approved for treatment of chronic myeloid leukemia, was demonstrated to have activities for solid tumors. Here, we report the differential sensitivity of dasatinib for HNSCC cells and identify the possible molecular events. Material and method: HNSCC cells including Ca9-22, HSC3, UMSCC1, FaDu, and SAS were treated with dasatinib. Cell viability, apoptosis, and underlined signal transduction were evaluated by MTT assay, flow cytometry and Western blotting, respectively. Results: Five HNSCC cells treated with dasatinib displayed differential sensitivities. Ca9-22 and HSC3 cells are the most sensitive cells in response to dasatinib and showed significant growth inhibition and apoptosis. In contrast, FaDu and SAS cells are resistant to dasatinib-induced growth inhibition and apoptosis. UMSCC1 cells showed intermediate sensitivity to dasatinib; their growth was inhibited without induction of apoptosis. Src inhibition (Y416 dephosphorylation) was observed in all 5 cells treated with dasatinib. The growth inhibition of Ca9-22, HSC3, and UMSCC1 cells was correlated with inhibition of Akt and Erk activities, which is not observed in SAS and FaDu cells. In addition, anti-apoptotic protein bcl-2 was increased in UMSCC1, FaDu, and SAS cells, but decreased in Ca9-22 and HSC3 cells. Therefore, the increases of bcl-2 in UMSCC1 may protect cells from dasatinib-induced apoptosis. Conclusion: Bcl-2 plays a crucial role in dasatinib-induced apoptosis in HNSCC cells, providing a new therapeutic approach to target bcl-2 in HNSCC treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1027. doi:10.1158/1538-7445.AM2011-1027
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