Seminar in KUTTAM, 19.04.2018, Buse Cevatemre

Author: Seminar in KUTTAM, 19.04.2018, Buse Cevatemre
Time: 13:00
Location: MED 176



Thursday, April 19th, 2018


Speaker:  Buse Cevatemre

Title:       A Possible Link Between The Mitochondrial Gatekeeper Pyruvate Dehydrogenase Enzyme Complex and EMT

Time:      13:00 (Refreshments will be served at 12:45)


A Possible Link Between The Mitochondrial Gatekeeper Pyruvate Dehydrogenase Enzyme Complex and EMT

Background: Recently, mitochondria have attracted much attention in metastatic cancer research. There are several reports showing that highly metastatic cancer cells preferentially use glycolysis over mitochondrial respiration for energy production. Pyruvate dehydrogenase enzyme complex (PDH), the gatekeeper enzyme of mitochondria is shown to be responsible for this switch in some cancers. Epithelial mesenchymal transition (EMT), has been proposed to be a driving force of metastasis. Therefore, revealing a connection between EMT and cancer cell metabolism may improve our understanding on metastasis. Although increments have been made in metastatic cancer research, there are no studies showing the relationship between PDH and EMT.

Methods: To inhibit PDH activity, pharmacological (PDH inhibitor, Cpi-613) and RNAi (stable cell lines were established by lentivirus) were used in A549 cells. The antiproliferative effect of Cpi-613 was investigated by xCELLigence System, SRB and ATP viability assays. Wound healing, invasion and drug sensitivity tests were applied at antiproliferative doses. To demonstrate the EMT phenotype in cells, the expression of EMT-related proteins (E-cadherin, N-cadherin, Vimentin, α-SMA) was analyzed via western blotting. Furhermore, SB-431542 (TGF-βRI inhibitor) was used to test whether Cpi-613 induced EMT depends on TGF-β signalling.

Results: Our results showed that both the inhibition of PDH by Cpi-613 and the knockdown of PDHA1 induced morphological changes, which were characteristics of EMT. A more rapid wound healing, increased invasive potential and chemoresistance were also shown. SB-431542 treatment reversed the EMT phenotype. The proportion of CD133+ cells were also higher in shPDHA1 cells than those of shControl cells.

Conclusions: Knockdown of PDHA1 expression or inhibition of PDH activity induced the EMT phenotype and more importantly resulted in resistance to chemotherapeutic drugs. Therefore, the use of Cpi-613 or PDH blockers becomes debatable for use in anticancer theraphy.

Funding: Turkish Scientific and Technical Research Council-TUBlTAK (Project Number: 115Z124) and Unit of Uludag University Scientific Research Projects (Project Number: DD(F)_2016/8)