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Gabapentin Can Suppress Cell Proliferation Independent of the Cytosolic Branched-Chain Amino Acid Transferase 1 (BCAT1).

Authors
  • Grankvist, Nina1, 2, 3
  • Lagerborg, Kim A4
  • Jain, Mohit4
  • Nilsson, Roland1, 2, 3
  • 1 Cardiovascular Medicine Unit, Department of Medicine, Solna , Karolinska Institutet , Stockholm SE-17176 , Sweden. , (Sweden)
  • 2 Karolinska University Hospital , Stockholm SE-17176 , Sweden. , (Sweden)
  • 3 Center for Molecular Medicine , Karolinska Institutet , Stockholm SE-17176 , Sweden. , (Sweden)
  • 4 Departments of Medicine and Pharmacology , University of California, San Diego , 9500 Gilman Drive , La Jolla , California 92093 , United States. , (United States)
Type
Published Article
Journal
Biochemistry
Publisher
American Chemical Society
Publication Date
Dec 11, 2018
Volume
57
Issue
49
Pages
6762–6766
Identifiers
DOI: 10.1021/acs.biochem.8b01031
PMID: 30427175
Source
Medline
Language
English
License
Unknown

Abstract

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.

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