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    A possible link between the mitochondrial gatekeeper pyruvate dehydrogenase enzyme complex and EMT
    (Science Direct, 2018) Cevatemre, B.; Dere, E.; Ulukaya, Engin
    Introduction In recent years, mitochondria have attracted much attention in metastatic cancer research. The first finding of the importance of mitochondria in cancer was reported by Otto Warburg in 1920. In the following years,it was found that cancer is closely related to mitochondrial characteristics such as glucose metabolism and chemoresistance. In this context,epithelial mesenchymal transition (EMT), due to its potential of being a molecular marker for tumour metastasis, clarification of this process is essential. Although increments have been made in metastatic cancer research,there are no studies showing the relationship between pyruvate dehydrogenase enzyme complex (PDH) and EMT.
  • Küçük Resim
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    Pyruvate dehydrogenase contributes to drug resistance of lung cancer cells through epithelial mesenchymal transition
    (Frontiers Media S.A., 2022) Cevatemre, B.; Ulukaya, Engin; Dere, E.; Dilege, S.; Açılan, C.
    Recently, there has been a growing interest on the role of mitochondria in metastatic cascade. Several reports have shown the preferential utilization of glycolytic pathway instead of mitochondrial respiration for energy production and the pyruvate dehydrogenase (PDH) has been considered to be a contributor to this switch in some cancers. Since epithelial mesenchymal transition (EMT) is proposed to be one of the significant mediators of metastasis, the molecular connections between cancer cell metabolism and EMT may reveal underlying mechanisms and improve our understanding on metastasis. In order to explore a potential role for PDH inhibition on EMT and associated drug resistance, we took both pharmacological and genetic approaches, and selectively inhibited or knocked down PDHA1 by using Cpi613 and shPDHA1, respectively. We found that both approaches triggered morphological changes and characteristics of EMT (increase in mesenchymal markers). This change was accompanied by enhanced wound healing and an increase in migration. Interestingly, cells were more resistant to many of the clinically used chemotherapeutics following PDH inhibition or PDHA1 knockdown. Furthermore, the TGF?RI (known as a major inducer of the EMT) inhibitor (SB-431542) together with the PDHi, was effective in reversing EMT. In conclusion, interfering with PDH induced EMT, and more importantly resulted in chemoresistance. Therefore, our study demonstrates the need for careful consideration of PDH-targeting approaches in cancer treatment. Copyright © 2022 Cevatemre, Ulukaya, Dere, Dilege and Acilan.