Suppression of pyruvate dehydrogenase kinase-2 re-sensitizes paclitaxel-resistant human lung cancer cells to paclitaxel.

TLDR: Results indicate that pac litaxel-induced expression of PDK2 serves as an important mechanism for acquired paclitaxel resistance of lung cancer cells, and highlight the importance ofPDK2 for potential therapeutic interventions in patients who have developed a resistance to paclitAXel.

Abstract: // Hong Sun 1 , Anyou Zhu 1 , Xiang Zhou 2 and Fengchao Wang 1 1 Department of Clinical Laboratory Science, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China 2 Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Correspondence to: Fengchao Wang, email: wfc123489@sina.com Xiang Zhou, email: zhouxiang1103@126.com Keywords: glycolysis, pyruvate dehydrogenase kinase-2, drug resistance, NSCLC Received: October 07, 2016     Accepted: January 24, 2017     Published: April 10, 2017 ABSTRACT Despite impressive initial clinical responses, the majority of lung cancer patients treated with paclitaxel eventually develop resistance to the drug. Pyruvate dehydrogenase kinase-2 (PDK2) is a key regulator of glycolysis and oxidative phosphorylation, and its expression is increased in a variety of tumors. In this study, the role of PDK2 in mediating paclitaxel resistance in lung cancer cells was investigated using biochemical and isotopic tracing methods. Increased expression of PDK2 was observed in paclitaxel-resistant cells ascompared totheir parental cells. Down-regulation of PDK2 usingsiRNA increased the sensitivity to paclitaxel of resistant lung cancer cells. Targeting paclitaxel-resistant cells throughPDK2 knockdown was associated with reduced glycolysis rather than increased oxidative phosphorylation (OXPHOS). Moreover, combining paclitaxel withthe specific PDK2 inhibitor dichloroacetate had a synergistic inhibitory effect on the viability of paclitaxel-resistant lung cancer cells. These results indicate that paclitaxel-induced expression of PDK2 serves as an important mechanism for acquired paclitaxel resistance of lung cancer cells. They also highlight the importance of PDK2 for potential therapeutic interventions in patients who have developed a resistance to paclitaxel.