Effects of Copper Chelation on BRAFV600E Positive Colon Carcinoma Cells
Effects of Copper Chelation on BRAFV600E Positive Colon Carcinoma Cells
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DOI：
10.3390/cancers11050659
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发表时间：
2019-05-01
期刊：
影响因子：
5.2
通讯作者：
Toietta, Gabriele
中科院分区：
文献类型：
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作者：
Baldari, Silvia;Di Rocco, Giuliana;Toietta, Gabriele
高亲和力铜与丝裂原激活蛋白激酶激酶 1 (MAP2K1，也称为 MEK1) 结合，以变构方式促进 MEK1/2 对细胞外信号调节激酶 1 和 2 (ERK1/2) 的激酶活性。因此，丝裂原激活（MAP）激酶途径的铜依赖性激活在促进肿瘤生长中发挥作用。相反，铜螯合可能代表针对特定亚型肿瘤的可能治疗方法，其特征是激活丝氨酸/苏氨酸蛋白激酶 V-Raf 鼠肉瘤病毒癌基因同源物 B1 (BRAF) 中的突变，例如 V600E，发生在激酶结构域 (BRAF(V600E)) 内。四硫代钼酸盐 (TM) 是一种特定的铜螯合剂，目前用于治疗威尔逊氏病和由于其抗血管生成和抗炎特性，用于治疗转移性癌症的临床前研究。我们在体外和体内评估了 TM 药物治疗在携带 BRAF(V600E) 突变的人结直肠细胞中与 BRAF 野生型细胞相比所实现的铜消耗效果。我们提供的证据表明，与 BRAF(wt) 相比，选择性铜螯合通过 ERK1/2 的不同磷酸化水平对携带 BRAF(V600E) 突变的结肠癌细胞的增殖、存活和迁移产生不同的影响。此外，四硫代钼酸盐治疗还可有效降低对 BRAF 药理抑制耐药的结肠癌 BRAF（V600E）细胞的克隆形成潜力。总之，这些结果支持进一步评估铜螯合疗法作为抑制含有 BRAF(V600E) 突变的结肠癌进展的辅助疗法。
High affinity copper binding to mitogen-activated protein kinase kinase 1 (MAP2K1, also known as MEK1) allosterically promotes the kinase activity of MEK1/2 on extracellular signal regulated kinases 1 and 2 (ERK1/2). Consequently, copper-dependent activation of the mitogen-activated (MAP) kinase pathway has a role in promoting tumor growth. Conversely, copper chelation may represent a possible therapeutic approach for a specific subset of tumors characterized by activating mutations in the serine/threonine protein kinase V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF), such as the V600E, occurring within the kinase domain (BRAF(V600E)) Tetrathiomolybdate (TM) is a specific copper chelating agent currently used for the treatment of Wilson's disease and in preclinical studies for the management of metastatic cancers owing to its anti-angiogenic and anti-inflammatory properties. We evaluated in vitro and in vivo the effects of copper depletion achieved by pharmacological treatment with TM in human colorectal cells bearing the BRAF(V600E) mutation in comparison with BRAF wild type cells. We provide evidence that selective copper chelation differentially affects proliferation, survival and migration of colon cancer cells bearing the BRAF(V600E) mutation compared to BRAF(wt) acting via differential phosphorylation levels of ERK1/2. Moreover, tetrathiomolybdate treatment was also effective in reducing the clonogenic potential of colon cancer BRAF(V600E) cells resistant to BRAF pharmacological inhibition. In conclusion, these results support further assessment of copper chelation therapy as an adjuvant therapy for inhibiting the progression of colon cancers containing the BRAF(V600E) mutation.