PMID- 29988033
OWN - NLM
STAT- MEDLINE
DCOM- 20191125
LR  - 20191125
IS  - 2041-4889 (Electronic)
VI  - 9
IP  - 7
DP  - 2018 Jul 9
TI  - alpha-ketoglutarate dehydrogenase inhibition counteracts breast cancer-associated 
      lung metastasis.
PG  - 756
LID - 10.1038/s41419-018-0802-8 [doi]
LID - 756
AB  - Metastasis formation requires active energy production and is regulated at 
      multiple levels by mitochondrial metabolism. The hyperactive metabolism of cancer 
      cells supports their extreme adaptability and plasticity and facilitates 
      resistance to common anticancer therapies. In spite the potential relevance of a 
      metastasis metabolic control therapy, so far, limited experience is available in 
      this direction. Here, we evaluated the effect of the recently described 
      alpha-ketoglutarate dehydrogenase (KGDH) inhibitor, (S)-2-[(2,6-dichlorobenzoyl) 
      amino] succinic acid (AA6), in an orthotopic mouse model of breast cancer 4T1 and 
      in other human breast cancer cell lines. In all conditions, AA6 altered Krebs 
      cycle causing intracellular alpha-ketoglutarate (alpha-KG) accumulation. Consequently, 
      the activity of the alpha-KG-dependent epigenetic enzymes, including the DNA 
      demethylation ten-eleven translocation translocation hydroxylases (TETs), was 
      increased. In mice, AA6 injection reduced metastasis formation and increased 5hmC 
      levels in primary tumours. Moreover, in vitro and in vivo treatment with AA6 
      determined an alpha-KG accumulation paralleled by an enhanced production of nitric 
      oxide (NO). This epigenetically remodelled metabolic environment efficiently 
      counteracted the initiating steps of tumour invasion inhibiting the 
      epithelial-to-mesenchymal transition (EMT). Mechanistically, AA6 treatment could 
      be linked to upregulation of the NO-sensitive anti-metastatic miRNA 200 family 
      and down-modulation of EMT-associated transcription factor Zeb1 and its CtBP1 
      cofactor. This scenario led to a decrease of the matrix metalloproteinase 3 
      (MMP3) and to an impairment of 4T1 aggressiveness. Overall, our data suggest that 
      AA6 determines an alpha-KG-dependent epigenetic regulation of the 
      TET-miR200-Zeb1/CtBP1-MMP3 axis providing an anti-metastatic effect in a mouse 
      model of breast cancer-associated metastasis.
FAU - Atlante, Sandra
AU  - Atlante S
AD  - Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe 
      University, 60596, Frankfurt am Main, Germany.
FAU - Visintin, Alessia
AU  - Visintin A
AD  - Laboratory of Transgenic Mouse Models, Candiolo Cancer Institute - FPO, IRCCS, 
      Candiolo, Italy.
AD  - Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di 
      Torino, 10125, Torino, Italy.
FAU - Marini, Elisabetta
AU  - Marini E
AD  - Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di 
      Torino, 10125, Torino, Italy.
FAU - Savoia, Matteo
AU  - Savoia M
AD  - Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe 
      University, 60596, Frankfurt am Main, Germany.
FAU - Dianzani, Chiara
AU  - Dianzani C
AD  - Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di 
      Torino, 10125, Torino, Italy.
FAU - Giorgis, Marta
AU  - Giorgis M
AD  - Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di 
      Torino, 10125, Torino, Italy.
FAU - Surun, Duran
AU  - Surun D
AD  - Laboratory of Transgenic Mouse Models, Candiolo Cancer Institute - FPO, IRCCS, 
      Candiolo, Italy.
FAU - Maione, Federica
AU  - Maione F
AD  - Laboratory of Transgenic Mouse Models, Candiolo Cancer Institute - FPO, IRCCS, 
      Candiolo, Italy.
AD  - Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di 
      Torino, 10125, Torino, Italy.
FAU - Schnutgen, Frank
AU  - Schnutgen F
AD  - Department of Medicine, Hematology/Oncology, Goethe University, 60596, Frankfurt, 
      Germany.
FAU - Farsetti, Antonella
AU  - Farsetti A
AD  - Istituto di Biologia Cellulare e Neurobiologia (IBCN), Consiglio Nazionale delle 
      Ricerche (CNR), 00143, Roma, Italy.
FAU - Zeiher, Andreas M
AU  - Zeiher AM
AD  - Internal Medicine Clinic III, Department of Cardiology, Goethe University, 
      Frankfurt am Main, Germany.
FAU - Bertinaria, Massimo
AU  - Bertinaria M
AD  - Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di 
      Torino, 10125, Torino, Italy.
FAU - Giraudo, Enrico
AU  - Giraudo E
AD  - Laboratory of Transgenic Mouse Models, Candiolo Cancer Institute - FPO, IRCCS, 
      Candiolo, Italy.
AD  - Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di 
      Torino, 10125, Torino, Italy.
FAU - Spallotta, Francesco
AU  - Spallotta F
AD  - Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe 
      University, 60596, Frankfurt am Main, Germany.
FAU - Cencioni, Chiara
AU  - Cencioni C
AD  - Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe 
      University, 60596, Frankfurt am Main, Germany. chcencioni@gmail.com.
AD  - Istituto di Biologia Cellulare e Neurobiologia (IBCN), Consiglio Nazionale delle 
      Ricerche (CNR), 00143, Roma, Italy. chcencioni@gmail.com.
FAU - Gaetano, Carlo
AU  - Gaetano C
AD  - Laboratorio di Epigenetica, Istituti Clinici Scientifici Maugeri, Via Maugeri 4, 
      27100, Pavia, Italy. carlo.gaetano@gmail.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180709
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Enzyme Inhibitors)
RN  - AB6MNQ6J6L (Succinic Acid)
RN  - EC 1.2.4.2 (Ketoglutarate Dehydrogenase Complex)
SB  - IM
MH  - Animals
MH  - Breast Neoplasms/*complications/drug therapy/*metabolism
MH  - Cell Adhesion/drug effects
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects
MH  - Enzyme Inhibitors/chemistry/*therapeutic use
MH  - Female
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - Ketoglutarate Dehydrogenase Complex/*metabolism
MH  - Lung Neoplasms/*drug therapy/*etiology/*metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Succinic Acid/chemistry/*therapeutic use
PMC - PMC6037705
COIS- The authors declare that they have no conflict of interest.
EDAT- 2018/07/11 06:00
MHDA- 2019/11/26 06:00
PMCR- 2018/07/09
CRDT- 2018/07/11 06:00
PHST- 2018/01/09 00:00 [received]
PHST- 2018/06/13 00:00 [accepted]
PHST- 2018/05/30 00:00 [revised]
PHST- 2018/07/11 06:00 [entrez]
PHST- 2018/07/11 06:00 [pubmed]
PHST- 2019/11/26 06:00 [medline]
PHST- 2018/07/09 00:00 [pmc-release]
AID - 10.1038/s41419-018-0802-8 [pii]
AID - 802 [pii]
AID - 10.1038/s41419-018-0802-8 [doi]
PST - epublish
SO  - Cell Death Dis. 2018 Jul 9;9(7):756. doi: 10.1038/s41419-018-0802-8.