Malonyl-CoA decarboxylase inhibition is selectively cytotoxic to human breast cancer cells

W. Zhou, Y. Tu, P. J. Simpson, F. P. Kuhajda

Research output: Contribution to journalArticle

Abstract

Fatty acid synthase (FAS) inhibition initiates selective apoptosis of cancer cells both in vivo and in vitro, which may involve malonyl-CoA metabolism. These findings have led to the exploration of malonyl-CoA decarboxylase (MCD) as a potential novel target for cancer treatment. MCD regulates the levels of cellular malonyl-CoA through the decarboxylation of malonyl-CoA to acetyl-CoA. Malonyl-CoA is both a substrate for FAS and an inhibitor of fatty acid oxidation acting as a metabolic switch between anabolic fatty acid synthesis and catabolic fatty acid oxidation. We now report that the treatment of human breast cancer (MCF7) cells with MCD small interference RNA (siRNA) reduces MCD expression and activity, reduces adenosine triphosphate levels, and is cytotoxic to MCF7 cells, but not to human fibroblasts. In addition, we synthesized a small-molecule inhibitor of MCD, 5-(Morpholine-4- carbonyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl] -amino-pentanoic acid methyl ester (MPA). Similar to MCD siRNA, MPA inhibits MCD activity in MCF7 cells, increases cellular malonyl-CoA levels and is cytotoxic to a number of human breast cancer cell lines in vitro. Taken together, these data indicate that MCD-induced cytotoxicity is likely mediated through malonyl-CoA metabolism. These findings support the hypothesis that MCD is a potential therapeutic target for cancer therapy.

Original languageEnglish (US)
Pages (from-to)2979-2987
Number of pages9
JournalOncogene
Volume28
Issue number33
DOIs
StatePublished - Aug 20 2009

Fingerprint

malonyl-CoA decarboxylase
Malonyl Coenzyme A
Breast Neoplasms
MCF-7 Cells
Fatty Acid Synthases
Fatty Acids
RNA Interference
Pentanoic Acids
Neoplasms
Acetyl Coenzyme A
Decarboxylation

Keywords

  • Apoptosis
  • Fatty acid metabolism
  • Fatty acid synthase
  • Malonyl-CoA
  • Malonyl-CoA decarboxylase

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Malonyl-CoA decarboxylase inhibition is selectively cytotoxic to human breast cancer cells. / Zhou, W.; Tu, Y.; Simpson, P. J.; Kuhajda, F. P.

In: Oncogene, Vol. 28, No. 33, 20.08.2009, p. 2979-2987.

Research output: Contribution to journalArticle

Zhou, W. ; Tu, Y. ; Simpson, P. J. ; Kuhajda, F. P. / Malonyl-CoA decarboxylase inhibition is selectively cytotoxic to human breast cancer cells. In: Oncogene. 2009 ; Vol. 28, No. 33. pp. 2979-2987.
@article{f5c12e88c2984f73ad0d55929b91b2ff,
title = "Malonyl-CoA decarboxylase inhibition is selectively cytotoxic to human breast cancer cells",
abstract = "Fatty acid synthase (FAS) inhibition initiates selective apoptosis of cancer cells both in vivo and in vitro, which may involve malonyl-CoA metabolism. These findings have led to the exploration of malonyl-CoA decarboxylase (MCD) as a potential novel target for cancer treatment. MCD regulates the levels of cellular malonyl-CoA through the decarboxylation of malonyl-CoA to acetyl-CoA. Malonyl-CoA is both a substrate for FAS and an inhibitor of fatty acid oxidation acting as a metabolic switch between anabolic fatty acid synthesis and catabolic fatty acid oxidation. We now report that the treatment of human breast cancer (MCF7) cells with MCD small interference RNA (siRNA) reduces MCD expression and activity, reduces adenosine triphosphate levels, and is cytotoxic to MCF7 cells, but not to human fibroblasts. In addition, we synthesized a small-molecule inhibitor of MCD, 5-(Morpholine-4- carbonyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl] -amino-pentanoic acid methyl ester (MPA). Similar to MCD siRNA, MPA inhibits MCD activity in MCF7 cells, increases cellular malonyl-CoA levels and is cytotoxic to a number of human breast cancer cell lines in vitro. Taken together, these data indicate that MCD-induced cytotoxicity is likely mediated through malonyl-CoA metabolism. These findings support the hypothesis that MCD is a potential therapeutic target for cancer therapy.",
keywords = "Apoptosis, Fatty acid metabolism, Fatty acid synthase, Malonyl-CoA, Malonyl-CoA decarboxylase",
author = "W. Zhou and Y. Tu and Simpson, {P. J.} and Kuhajda, {F. P.}",
year = "2009",
month = "8",
day = "20",
doi = "10.1038/onc.2009.160",
language = "English (US)",
volume = "28",
pages = "2979--2987",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "33",

}

TY - JOUR

T1 - Malonyl-CoA decarboxylase inhibition is selectively cytotoxic to human breast cancer cells

AU - Zhou, W.

AU - Tu, Y.

AU - Simpson, P. J.

AU - Kuhajda, F. P.

PY - 2009/8/20

Y1 - 2009/8/20

N2 - Fatty acid synthase (FAS) inhibition initiates selective apoptosis of cancer cells both in vivo and in vitro, which may involve malonyl-CoA metabolism. These findings have led to the exploration of malonyl-CoA decarboxylase (MCD) as a potential novel target for cancer treatment. MCD regulates the levels of cellular malonyl-CoA through the decarboxylation of malonyl-CoA to acetyl-CoA. Malonyl-CoA is both a substrate for FAS and an inhibitor of fatty acid oxidation acting as a metabolic switch between anabolic fatty acid synthesis and catabolic fatty acid oxidation. We now report that the treatment of human breast cancer (MCF7) cells with MCD small interference RNA (siRNA) reduces MCD expression and activity, reduces adenosine triphosphate levels, and is cytotoxic to MCF7 cells, but not to human fibroblasts. In addition, we synthesized a small-molecule inhibitor of MCD, 5-(Morpholine-4- carbonyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl] -amino-pentanoic acid methyl ester (MPA). Similar to MCD siRNA, MPA inhibits MCD activity in MCF7 cells, increases cellular malonyl-CoA levels and is cytotoxic to a number of human breast cancer cell lines in vitro. Taken together, these data indicate that MCD-induced cytotoxicity is likely mediated through malonyl-CoA metabolism. These findings support the hypothesis that MCD is a potential therapeutic target for cancer therapy.

AB - Fatty acid synthase (FAS) inhibition initiates selective apoptosis of cancer cells both in vivo and in vitro, which may involve malonyl-CoA metabolism. These findings have led to the exploration of malonyl-CoA decarboxylase (MCD) as a potential novel target for cancer treatment. MCD regulates the levels of cellular malonyl-CoA through the decarboxylation of malonyl-CoA to acetyl-CoA. Malonyl-CoA is both a substrate for FAS and an inhibitor of fatty acid oxidation acting as a metabolic switch between anabolic fatty acid synthesis and catabolic fatty acid oxidation. We now report that the treatment of human breast cancer (MCF7) cells with MCD small interference RNA (siRNA) reduces MCD expression and activity, reduces adenosine triphosphate levels, and is cytotoxic to MCF7 cells, but not to human fibroblasts. In addition, we synthesized a small-molecule inhibitor of MCD, 5-(Morpholine-4- carbonyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl] -amino-pentanoic acid methyl ester (MPA). Similar to MCD siRNA, MPA inhibits MCD activity in MCF7 cells, increases cellular malonyl-CoA levels and is cytotoxic to a number of human breast cancer cell lines in vitro. Taken together, these data indicate that MCD-induced cytotoxicity is likely mediated through malonyl-CoA metabolism. These findings support the hypothesis that MCD is a potential therapeutic target for cancer therapy.

KW - Apoptosis

KW - Fatty acid metabolism

KW - Fatty acid synthase

KW - Malonyl-CoA

KW - Malonyl-CoA decarboxylase

UR - http://www.scopus.com/inward/record.url?scp=69249202281&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=69249202281&partnerID=8YFLogxK

U2 - 10.1038/onc.2009.160

DO - 10.1038/onc.2009.160

M3 - Article

C2 - 19543323

AN - SCOPUS:69249202281

VL - 28

SP - 2979

EP - 2987

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 33

ER -