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Combinatorial Effects of PK11195 and 5‐Azacytidine as an Epigenetic Modulator For MPC1
Author(s) -
Duran Daniel,
O'Donnell Robert Watts
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.595.14
Subject(s) - oxidative phosphorylation , glycolysis , warburg effect , mitochondrion , gene expression , microbiology and biotechnology , epigenetics , cell culture , chemistry , anaerobic glycolysis , biology , biochemistry , metabolism , gene , genetics
According to the Warburg effect, cancer cells typically favor glycolysis over oxidative phosphorylation wherein only a few select molecules of pyruvate are oxidized. The mitochondrial pyruvate carrier, MPC, contributes significantly to proper cellular respiration and its under expression correlates strongly with the observed “fractional pyruvate oxidation.” The associated MPC1 gene is under expressed or even deleted across multiple tumor cell lines, contributing to their preference of glycolysis as an energy supplying mechanism. We hope to reverse the Warburg effect by enhancing MPC1 gene expression and thereby increase the potential for tumor cells to undergo oxidative phosphorylation following glycolysis. Use of the DNA methyltransferase inhibitor 5‐azacytidine may, through its role as an epigenetic modulator, contribute to enhanced expression or even re‐expression of the MPC1 gene. An additional drug, PK11195, was chosen for its role as a peripheral benzodiazepine receptor ligand to similarly observe it potential effect on MPC1 expression. The drug itself binds with nanomolar affinity to the PBR on the outer mitochondrial membrane and alters mitochondrial respiration. Through qRT‐PCR we have demonstrated an increased expression of MPC1 in the HTB‐4 cell line upon co‐treatment with PK11195 and 5‐azacytidine over either drug used alone. This suggests the cells are navigating from glycolysis to an oxidative pathway in which MPC1 is an integral part. Experiments are planned to verify whether or not the MPC‐1 gene is similarly up regulated in other tumor cell lines; furthermore, we will investigate if the treated cells show an increase in reactive oxygen species, indicating a transition to oxidative phosphorylation. Support or Funding Information The Geneseo Foundation and the SUNY Geneseo Biology Department.