KIF11 is required for proliferation and self-renewal of docetaxel resistant triple negative breast cancer cells.
KIF11 is required for proliferation and self-renewal of docetaxel resistant triple negative breast cancer cells.
复制标题
DOI：
10.18632/oncotarget.20785
复制
发表时间：
2017-11-03
期刊：
影响因子：
--
通讯作者：
Zhuang Z
中科院分区：
文献类型：
--
作者：
Jiang M;Zhuang H;Xia R;Gan L;Wu Y;Ma J;Sun Y;Zhuang Z
化疗耐药性的发展仍然是三阴性乳腺癌治疗的主要障碍。以往的研究表明，具有自我更新和肿瘤启动能力的肿瘤干细胞亚群CD 44 +/CD 24-细胞是三阴性乳腺癌化疗耐药和治疗失败的部分原因。因此，靶向癌症干细胞（CSC）的新型药物可能会改善临床结果。KIF 11（kinesin family member 11，驱动蛋白家族成员11）是一种在有丝分裂中起重要作用的分子马达蛋白，在许多癌细胞中过表达。在这项研究中，我们评估其在多西他赛耐药的三阴性乳腺癌（TNBC）中的作用。我们发现KIF 11在多西他赛耐药的TNBC细胞的CD 44 +/CD 24-亚群中的表达显著增加。KIF 11的敲除导致CSC和乳腺球形成的百分比显著降低。KIF 11敲除还抑制细胞生长并诱导细胞周期G2/M停滞，随后是细胞有丝分裂和凋亡。进一步的多西他赛抗性TNBC异种移植物模型证明KIF 11抑制剂在体内发挥生长抑制作用。值得注意的是，我们还发现KIF 11在TNBC中高度表达，并且其表达与较短的无病生存时间相关。所有这些数据表明，KIF 11对于体外和体内TNBC肿瘤细胞的增殖和自我更新至关重要，表明KIF 11可能是治疗化疗耐药TNBC的有希望的治疗靶点。
Development of chemoresistance remains a major hurdle for triple negative breast cancer treatment. Previous studies suggest that CD44+/CD24- cells, subpopulation of cancer stem cells with self-renewing and tumor-initiating capacities, are partly responsible for chemoresistance and therapeutic failure of triple negative breast cancer. Therefore, novel agents that target cancer stem cells (CSCs) may improve the clinical outcome. KIF11 (kinesin family member 11), overexpressed in many cancer cells, is a molecular motor protein that plays essential role in mitosis. In this study, we assess its role in docetaxel resistant triple negative breast cancer (TNBC). We found that the expression of KIF11 was significantly increased in CD44+/CD24- subpopulation of docetaxel resistant TNBC cells. Knockdown of KIF11 resulted in a significant decrease in the percentage of CSCs and mammosphere formation. KIF11 knockdown also inhibits cell growth and induces cell cycle G2/M arrest followed by cell mitosis and apoptosis. Further docetaxel resistant TNBC xenograft models demonstrated that KIF11 inhibitor exerts growth inhibitory effect in vivo. Of note, we also found that KIF11 was highly expressed in TNBC and its expression was correlated with shorter disease free survival time. All these data indicate that KIF11 is critical for proliferation and self-renewal in TNBC tumor cells in vitro and in vivo, suggesting that KIF11 may be a promising therapeutic target for treating chemoresistant TNBC.