Jiang Meng, Zhuang Huiru, Xia Rui, Gan Lei, Wu Yuantao, Ma Junzhe, Sun Yihui, Zhuang Zhixiang
Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
Institute of Radiotherapy and Oncology, Soochow University, Suzhou, 215004, China.
Oncotarget. 2017 Sep 8;8(54):92106-92118. doi: 10.18632/oncotarget.20785. eCollection 2017 Nov 3.
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 . 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 and , suggesting that KIF11 may be a promising therapeutic target for treating chemoresistant TNBC.
化疗耐药的产生仍然是三阴性乳腺癌治疗的一个主要障碍。先前的研究表明，CD44+/CD24-细胞作为具有自我更新和肿瘤起始能力的癌症干细胞亚群，在一定程度上导致了三阴性乳腺癌的化疗耐药和治疗失败。因此，靶向癌症干细胞（CSCs）的新型药物可能会改善临床疗效。KIF11（驱动蛋白家族成员11）在许多癌细胞中过表达，是一种在有丝分裂中起关键作用的分子运动蛋白。在本研究中，我们评估了它在多西他赛耐药的三阴性乳腺癌（TNBC）中的作用。我们发现，在多西他赛耐药的TNBC细胞的CD44+/CD24-亚群中，KIF11的表达显著增加。敲低KIF11导致癌症干细胞百分比和乳腺球形成显著降低。敲低KIF11还抑制细胞生长并诱导细胞周期G2/M期阻滞，随后导致细胞有丝分裂和凋亡。进一步的多西他赛耐药TNBC异种移植模型表明，KIF11抑制剂具有生长抑制作用。值得注意的是，我们还发现KIF11在TNBC中高表达，其表达与无病生存期缩短相关。所有这些数据表明，KIF11对TNBC肿瘤细胞的增殖和自我更新至关重要，这表明KIF11可能是治疗化疗耐药TNBC的一个有前景的治疗靶点。
