JNK pathway desensitizes tumor cells to chemotherapy through modulating BMI-1 and NANOG protein stability in lung adenocarcinoma

• Main Authors: Po-Hung Chen, 陳柏宏
• Other Authors: Cheng-Wen Wu
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/5ujcu9

碩士 === 國立陽明大學 === 臨床醫學研究所 === 103 === Lung cancer is the leading cause of cancer mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for about 80% of lung cancers, among which the lung adenocarcinoma (LAC) is the most common histological subtype (about 40%). LAC is frequently associated with activating epidermal growth factor receptor (EGFR) mutations, and chemotherapy has limited efficacy. BMI-1 and NANOG are stemness factors that have been suggested to regulate tumor initiation, invasion, and drug resistance in different types of cancer. The role and importance of BMI-1 and NANOG in lung cancer, however, have not been well identified. In our study, we found that BMI-1 and NANOG were regulated in LAC by JNK, a stress-activated protein kinase. JNK can be activated by either EGFR signaling or chemotherapy-induced DNA damage. Treatment with EGF or chemotherapy drugs in LAC induced JNK phosphorylation and the enhanced the expressions of BMI-1 and NANOG. Instead, knockdown of JNK by shRNA reduced the basal level of BMI-1 and NANOG, and also blocked their inductions by EGF or chemotherapy drugs. Further investigations showed that JNK pathway positively regulates BMI-1 through enhancing their protein stability. A novel E3-ligase, HUWE1, was identified to mediate the ubiquitination of BMI-1, which may be regulated by the activation of JNK pathway. Knockdown of BMI-1 and JNK made LAC cells more sensitive to chemotherapeutics. A compound X was identified from Connectivity Map, which can inhibit the protein levels of BMI-1 and NANOG, and also sensitized LAC cells to chemotherapy. In summary, our results showed that the activation of JNK pathway in LAC can stabilize and enhance the protein levels of BMI-1 and NANOG, and improved LAC cell survival against chemotherapeutic agents treatment. Inhibition of JNK pathway or BMI-1/NANOG by compound X may be combined with chemotherapy for the treatment of LAC.