Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan.
Neoplasia. 2012 Jun;14(6):463-75. doi: 10.1596/neo.12300.
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.
表皮生长因子受体（EGFR）是一种重要的癌蛋白，可促进细胞生长和增殖。Dasatinib 是一种 bcr-abl 抑制剂，已在临床上被批准用于治疗慢性髓性白血病，并通过抑制 Src 被证明在体外对实体瘤有效。在这里，我们揭示了 EGFR 降解介导的 Dasatinib 诱导头颈部鳞状细胞癌（HNSCC）细胞凋亡。用 Dasatinib 处理包括 Ca9-22、FaDu、HSC3、SAS、SCC-25 和 UMSCC1 在内的 HNSCC 细胞，评估细胞活力、凋亡和潜在的信号转导。Dasatinib 对 HNSCC 细胞表现出不同的敏感性。生长抑制和凋亡与 Akt、Erk 和 Bcl-2 的抑制相关，而与 Src 抑制无关。因此，我们发现 EGFR 的下调是 Dasatinib 敏感性的决定因素。溶酶体抑制剂逆转了 Dasatinib 诱导的 EGFR 下调，并且 Dasatinib 增加了 c-cbl 的活性，表明 Dasatinib 诱导的 EGFR 下调可能是通过 c-cbl 介导的溶酶体降解。配体给药增加 EGFR 激活可使细胞免于 Dasatinib 诱导的凋亡，而 EGFR 抑制增强了其凋亡作用。雌激素受体α（ERα）被证明在 Bcl-2 表达中起作用，Dasatinib 在翻译前水平抑制 ERα。Dasatinib 处理的 HNSCC 细胞中 ERα 与 EGFR 相关。此外，异种移植模型表明，Dasatinib 通过体内下调 EGFR 和 ERα 抑制 HSC3 肿瘤生长。总之，EGFR 的降解是 Dasatinib 诱导 HNSCC 细胞凋亡的一种新机制。
