posted on 2018-11-14, 00:00authored byNina Grankvist, Kim A. Lagerborg, Mohit Jain, Roland Nilsson
The
metabolism of branched-chain amino acids (BCAA) has recently
been implicated in the growth of several cancer cell types. Gabapentin,
a synthetic amino acid, is commonly used in high concentrations in
this context to inhibit the cytosolic branched-chain amino acid transferase
(BCAT1) enzyme. Here, we report that 10 mM gabapentin reduces the
growth of HCT116 cells, which have an active branched-chain amino
acid transferase but express very low levels of BCAT1, and presumably
rely on the mitochondrial BCAT2 enzyme. Gabapentin did not affect
transamination of BCAA to branched-chain keto acids (BCKA) in HCT116
cells, nor the reverse formation of BCAA from BCKA, indicating that
the branched-chain amino acid transaminase is not inhibited. Moreover,
the growth-inhibitory effect of gabapentin could not be rescued by
supplementation with BCKA, and this was not due to the lack of uptake
of BCKA, indicating that other effects of gabapentin are important.
An untargeted LC–MS analysis of gabapentin-treated cells revealed
a marked depletion of branched-chain carnitines. These results demonstrate
that gabapentin at high concentrations can inhibit cell proliferation
without affecting BCAT1 and may affect mitochondrial BCKA catabolism.