Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Toxicon. 2012 Oct;60(5):734-43. doi: 10.1016/j.toxicon.2012.05.019. Epub 2012 Jun 7.
Cardiotoxin III (CTX III), a basic polypeptide isolated from Naja naja atra venom, has been shown to exhibit anticancer activity. Epidermal growth factor (EGF) and its receptor, EGFR, play roles in cancer metastasis in various tumors. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of CTX III on cell migration. CTX III inhibited the EGF-induced activation of matrix metalloproteinase-9 (MMP-9), and further suppressed cell invasion and migration without obvious cellular cytotoxicity. CTX III suppressed EGF-induced nuclear factor-kappaB (NF-κB) nuclear translocation and also abrogated the EGF-induced phosphorylation of EGFR, phosphatidylinositol 3-kinase (PI3K)/Akt, and extracellular regulated kinase (ERK)1/2. In addition, CTX III similar to wortmannin (a PI3K inhibitor) and U0126 (an up-stream kinase regulating ERK1/2 inhibitor) attenuated cell migration and invasion induced by EGF. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of ERK1/2 and PI3K/Akt, suggesting that ERK1/2 and PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that CTX III inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt, ERK1/2, and NF-κB signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of CTX III as a potent anti-metastatic agent in MDA-MB-231 cells.
细胞毒素 III（CTX III）是从中华眼镜蛇毒液中分离得到的一种碱性多肽，已被证明具有抗癌活性。表皮生长因子（EGF）及其受体 EGFR 在多种肿瘤的癌症转移中发挥作用。我们使用 EGF 作为 MDA-MB-231 细胞的转移诱导剂，研究 CTX III 对细胞迁移的影响。CTX III 抑制 EGF 诱导的基质金属蛋白酶-9（MMP-9）的激活，并且在没有明显细胞毒性的情况下进一步抑制细胞侵袭和迁移。CTX III 抑制 EGF 诱导的核因子-κB（NF-κB）核易位，并且还阻断 EGF 诱导的 EGFR、磷酸肌醇 3-激酶（PI3K）/Akt 和细胞外调节激酶（ERK）1/2 的磷酸化。此外，CTX III 类似于 wortmannin（一种 PI3K 抑制剂）和 U0126（一种调节 ERK1/2 的上游激酶抑制剂），减弱了 EGF 诱导的细胞迁移和侵袭。此外，EGFR 抑制剂 AG1478 抑制了 EGF 诱导的 MMP-9 表达、细胞迁移和侵袭以及 ERK1/2 和 PI3K/Akt 的激活，表明 ERK1/2 和 PI3K/Akt 的激活发生在 EGFR 激活的下游。这些发现表明，CTX III 通过 EGFR 依赖性 PI3K/Akt、ERK1/2 和 NF-κB 信号通路抑制 EGF 诱导的 MDA-MB-231 细胞的侵袭和迁移，导致 MMP-9 表达下调。这些结果提供了一种新的机制来解释 CTX III 作为 MDA-MB-231 细胞中一种有效的抗转移剂的作用。
