Panneerselvam Janani, Mohandoss Priyanga, Patel Ravi, Gillan Hamza, Li Michael, Kumar Kirtana, Nguyen DangHuy, Weygant Nathaniel, Qu Dongfeng, Pitts Kamille, Lightfoot Stanley, Rao Chinthalapally, Houchen Courtney, Bronze Michael, Chandrakesan Parthasarathy
Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Department of Biomedical Engineering, SRM University, Chennai, India.
Mol Ther Oncolytics. 2020 May 27;18:24-36. doi: 10.1016/j.omto.2020.05.012. eCollection 2020 Sep 25.
Chemoresistance cells have features similar to cancer stem cells. Elimination of these cells is an effective therapeutic strategy to clinically combat chemoresistance non-small cell lung cancer (NSCLC). Here, we demonstrate that () is the key to developing chemoresistance and associated stemness in NSCLC. DCLK1 is highly expressed in human lung adenocarcinoma and strongly correlated with stemness. Silencing inhibits NSCLC cell primary and secondary spheroid formation, which is the prerequisite feature of tumor stem cells. inhibition reduced NSCLC cell migration/invasion and induced tumor growth inhibition . NSCLC cells responded differently to cisplatin treatment; indeed, the clonogenic ability of all NSCLC cells was reduced. We found that the cisplatin-resistant NSCLC cells gain the expression of DCLK1 compared with their parental control. However, inhibition in cisplatin-resistance NSCLC cells reverses the tumor cell resistance to cisplatin and reduced tumor self-renewal ability. Specifically, we found that -mediated cisplatin resistance in NSCLC is via an ()-dependent mechanism. Our data demonstrate that increased expression of is associated with chemoresistance and enhanced cancer stem cell-like features in NSCLC. Targeting using gene knockdown/knockout strategies alone or in combination with cisplatin may represent a novel therapeutic strategy to treat NSCLC.
化疗耐药细胞具有与癌症干细胞相似的特征。清除这些细胞是临床上对抗非小细胞肺癌（NSCLC）化疗耐药的一种有效治疗策略。在此，我们证明（）是NSCLC中产生化疗耐药和相关干性的关键。DCLK1在人肺腺癌中高表达，且与干性密切相关。沉默（）可抑制NSCLC细胞原发性和继发性球体形成，而这是肿瘤干细胞的必备特征。（）抑制可降低NSCLC细胞迁移/侵袭能力并诱导肿瘤生长抑制。NSCLC细胞对顺铂治疗反应不同；事实上，所有NSCLC细胞的克隆形成能力均降低。我们发现，与亲本对照相比，顺铂耐药的NSCLC细胞获得了DCLK1的表达。然而，在顺铂耐药的NSCLC细胞中抑制（）可逆转肿瘤细胞对顺铂的耐药性并降低肿瘤自我更新能力。具体而言，我们发现NSCLC中（）介导的顺铂耐药是通过一种（）依赖性机制。我们的数据表明，（）表达增加与NSCLC的化疗耐药和增强的癌症干细胞样特征相关。单独使用基因敲低/敲除策略或与顺铂联合靶向（）可能代表一种治疗NSCLC的新型治疗策略。
