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

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.

Polymorphisms in Glycolysis-Related Genes Are Associated with Clinical Outcomes of Paclitaxel-Cisplatin Chemotherapy in Non-Small Cell Lung Cancer

“…Cisplatin-resistance has been linked to an increased dependence on glycolysis and pentose phosphate pathway [21,37,38]. Studies also showed that enhanced glycolysis is associated with paclitaxel resistance and that inhibition of glycolysis could reverse the drug resistance [39][40][41]. Along with these studies, our findings add to the evidence that aerobic glycolysis plays a significant role in determining clinical outcomes of paclitaxelcisplatin chemotherapy in NSCLC.…”

Long noncoding RNA DUXAP8 contributes to the progression of hepatocellular carcinoma via regulating miR‐422a/PDK2 axis

“…By reducing the conversion of pyruvate to acetyl‐CoA, PDK2 switches carbon flow from the tricarboxylic acid cycle and de novo lipogenesis to lactate production, thus facilitating Warburg effect . Dysregulation of PDK2 is reported in multiple cancers, and linked to proliferation, metastasis, and chemoresistance of cancer cells . Specifically, in HCC, PDK2 is identified as target of miR‐214, and involved in disease progression .…”

“…33 Dysregulation of PDK2 is reported in multiple cancers, and linked to proliferation, metastasis, and chemoresistance of cancer cells. [34][35][36][37] Specifically, in HCC, PDK2 is identified as target of miR-214, and involved in disease progression. 37 Recently, PDK2 has been proved to be negatively regulated by miR-422a, and PDK2 inhibition by miR-422a results in increased activity of the pyruvate dehydrogenase and higher acetyl-CoA level.…”

The Influence of Metabolism on Drug Response in Cancer

“…Lung cancer cells that are resistant to carboplatin, which has a similar mode of action, are more dependent on glycolysis ( 106 ). In addition, paclitaxel-resistant lung cancer cells show higher expression of PDK2 as compared to their parental cells ( 105 ). As a result, these resistant cells are more dependent on glycolysis than OXPHOS and could be sensitized to paclitaxel through PDK2 inhibition.…”