Boufraqech Myriem, Wei Darmood, Weyemi Urbain, Zhang Lisa, Quezado Martha, Kalab Petr, Kebebew Electron
Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Urology Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Oncotarget. 2016 May 17;7(20):29023-35. doi: 10.18632/oncotarget.8628.
LOX regulates cancer progression in a variety of human malignancies. It is overexpressed in aggressive cancers and higher expression of LOX is associated with higher cancer mortality. Here, we report a new function of LOX in mitosis. We show that LOX co-localizes to mitotic spindles from metaphase to telophase, and p-H3(Ser10)-positive cells harbor strong LOX staining. Further, purification of mitotic spindles from synchronized cells show that LOX fails to bind to microtubules in the presence of nocodazole, whereas paclitaxel treated samples showed enrichment in LOX expression, suggesting that LOX binds to stabilized microtubules. LOX knockdown leads to G2/M phase arrest; reduced p-H3(Ser10), cyclin B1, CDK1, and Aurora B. Moreover, LOX knockdown significantly increased sensitivity of cancer cells to chemotherapeutic agents that target microtubules. Our findings suggest that LOX has a role in cancer cell mitosis and may be targeted to enhance the activity of microtubule inhibitors for cancer therapy.
赖氨氧化酶（LOX）在多种人类恶性肿瘤中调节癌症进展。它在侵袭性癌症中过度表达，且LOX的高表达与更高的癌症死亡率相关。在此，我们报道了LOX在有丝分裂中的新功能。我们发现，从中期到末期，LOX与有丝分裂纺锤体共定位，并且p-H3（Ser10）阳性细胞有强烈的LOX染色。此外，从同步化细胞中纯化有丝分裂纺锤体表明，在诺考达唑存在的情况下，LOX无法与微管结合，而紫杉醇处理的样本显示LOX表达富集，这表明LOX与稳定的微管结合。敲低LOX会导致G2/M期阻滞；降低p-H3（Ser10）、细胞周期蛋白B1、细胞周期蛋白依赖性激酶1（CDK1）和极光激酶B（Aurora B）的水平。此外，敲低LOX显著增加了癌细胞对靶向微管的化疗药物的敏感性。我们的研究结果表明，LOX在癌细胞有丝分裂中起作用，并且可能成为增强微管抑制剂治疗癌症活性的靶点。
