Evaluation the Effect of TOPK Inhibitor in Lung Cancer Xenograft Model and Exploration the Function of TOPK via Gene Expression Profiling

• Main Authors: YANG, YUN-HSUAN, 楊允瑄
• Other Authors: LAI, JIN-MEI
• Format: Others
• Language: zh-TW
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/30587620908439455852

碩士 === 輔仁大學 === 生命科學系碩士班 === 105 === Lung cancer ranks among the most deadly cancers worldwide. Despite the discovery of oncogenic driver mutation has leaded to develop novel molecular therapeutics, chemotherapy remains the mainstay of treatment for advanced patients without a known driver mutation. Therefore, identification of a new treatment strategy is still necessary. PBK/TOPK (PDZ-binding kinase/lymphokine-activated killer T cell-originated protein kinase), a serine-threonine kinase that is highly expressed in lung cancer cells, is involved in cancer cell proliferation and metastasis. Here, this thesis aim to evaluate the potential of TOPK inhibitor in lung cancer treatment. To identify the novel mechanism that may be involved in TOPK-mediated oncogenesis, I firstly utilized LINCS database to quarry the drug(s) that may conduct gene perturbation with high similarity as compared to TOPK knockdown (shTOPK). Among the drug list, I focused on FK866 (NAMPT inhibitor) and PF04217903- (c-Met inhibitor) for further investigation. Since TOPK inhibitor did not significantly affect the expression of NAMPT and NAD+/NADH level, TOPK may not regulate NAMPT to conduct tumorigenesis. However, FK866 can inhibit the growth of A549 and CL97 lung cancer cells and concurrently decrease of p-TOPK and p-Histone H3 at 48 or 72 hrs, indicating FK866 elicited growth inhibitory effect may at least partially through inhibition of TOPK. In addition, TOPK inhibitor indeed decreased c-Met or c-Met phosphorylation in lung cancer cells. Furthermore, TOPK inhibitor alone or in combination with cisplatin can inhibit the growth of lung cancer cells in vitro and in vivo. Lastly, TOPK inhibitor may also act as an anti-CSCs agent, by its inhibition of lung cancer sphere cells and decrease CSCs markers, such as CD133 and SOX2. Overall, these findings extend our understanding of TOPK function and set the stage for TOPK inhibitor in clinical use for lung cancer treatment.