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.
Highlights
Non-smallcell lung cancer (NSCLC) is one of the most common malignant tumors and a leading cause of mortality worldwide
A549-R cells showed increased sensitivity to paclitaxel compared to A549-R1 and their parental A549 cells(Figure 3F). These results indicate that paclitaxel resistance is associated with increased Pyruvate dehydrogenase kinase-2 (PDK2) expression and that knockdown of PDK2 may re-sensitize A549-R andA549-R1cells to paclitaxel
In comparison to paclitaxel-sensitive cells, PDK2 expression was increased in paclitaxel-resistant cells
Summary
Non-smallcell lung cancer (NSCLC) is one of the most common malignant tumors and a leading cause of mortality worldwide. Paclitaxel (Taxol), which targets microtubules of cancer cells, has been widely used in cancertreatment [1, 2]. Paclitaxel disrupts the dynamic equilibrium between soluble tubulin dimers and their polymerized form to stabilize the microtubule structure. Paclitaxel is an effective inhibitor of chromosomal replication by obstructing cancer cells in the late G2 or mitotic phases [3]. The efficiency of paclitaxel-based chemotherapy is limited by the development of acquired resistance. Increasedexpression of multidrug resistant proteins and anti-apoptotic proteins isthe main cause of paclitaxel resistance [4]. The specific molecular mechanisms involved in paclitaxel resistance are complex and not completely understood
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