Specific inhibition by synthetic analogs of pyruvate reveals that the pyruvate dehydrogenase reaction is essential for metabolism and viability of glioblastoma cellsстатья
Статья опубликована в высокорейтинговом журнале
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Дата последнего поиска статьи во внешних источниках: 20 января 2016 г.
Аннотация:The pyruvate dehydrogenase complex (PDHC) and its phosphorylation are
considered essential for oncotransformation, but it is unclear whether cancer cells
require PDHC to be functional or silenced. We used specific inhibition of PDHC by
synthetic structural analogs of pyruvate to resolve this question. With isolated and
intramitochondrial PDHC, acetyl phosphinate (AcPH, Ki
AcPH = 0.1 μM) was a much more
potent competitive inhibitor than the methyl ester of acetyl phosphonate (AcPMe, Ki
AcPMe
= 40 μM). When preincubated with the complex, AcPH also irreversibly inactivated
PDHC. Pyruvate prevented, but did not reverse the inactivation. The pyruvate analogs
did not significantly inhibit other 2-oxo acid dehydrogenases. Different cell lines were
exposed to the inhibitors and a membrane-permeable precursor of AcPMe, dimethyl
acetyl phosphonate, which did not inhibit isolated PDHC. Using an ATP-based assay,
dependence of cellular viability on the concentration of the pyruvate analogs was
followed. The highest toxicity of the membrane-permeable precursor suggested
that the cellular action of charged AcPH and AcPMe requires monocarboxylate
transporters. The relevant cell-specific transcripts extracted from Gene Expression
Omnibus database indicated that cell lines with higher expression of monocarboxylate
transporters and PDHC components were more sensitive to the PDHC inhibitors. Prior
to a detectable antiproliferative action, AcPH significantly changed metabolic profiles
of the investigated glioblastoma cell lines. We conclude that catalytic transformation
of pyruvate by pyruvate dehydrogenase is essential for the metabolism and viability
of glioblastoma cell lines, although metabolic heterogeneity causes different cellular
sensitivities and/or abilities to cope with PDHC inhibition.