Fatty acid synthesis

A potential selective target for antineoplastic therapy

Francis P. Kuhajda, Kris Jenner, Fawn D. Wood, Randolph A. Hennigar, Lisa B. Jacobs, James D. Dick, Gary R. Pasternack

Research output: Contribution to journalArticle

Abstract

OA-519 is a prognostic molecule found in tumor cells from breast cancer patients with markedly worsened prognosis. We purified OA-519 from human breast carcinoma cells, obtained its peptide sequence, and unambiguously identified it as fatty acid synthase through sequence homology and enzymology. Tumor fatty acid synthase is an ≃270-kDa polypeptide which specifically abolished immunostaining of human breast cancers by anti-OA-519 antibodies. Tumor fatty acid synthase oxidized NADPH in a malonyl-CoA- dependent fashion and synthesized fatty acids composed of 80% palmitate, 10% myristate, and 10% stearate from acetyl-CoA, malonyl-CoA, and NADPH with a specific activity of 624 nmol of NADPH oxidized per min per mg. Tumor cell lines with elevated fatty acid synthase showed commensurate increases in incorporation of [U-14C]acetate into acylglycerols demonstrating that fatty acid synthase increases occur in the context of overall increases in endogenous fatty acid synthesis. Cerulenin inhibited acylglycerol synthesis in tumor cells and fibroblast controls in a dose-dependent fashion and also caused a growth inhibition which generally paralleled the level of endogenous fatty acid synthesis. Supraphysiologic levels of palmitate, 14 μM in dimethyl sulfoxide, significantly reversed the growth inhibition caused by cerulenin at concentrations of up to 5 μg/ml, indicating that cerulenin- mediated growth inhibition was due to fatty acid synthase inhibition.

Original languageEnglish (US)
Pages (from-to)6379-6383
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number14
DOIs
StatePublished - Jul 5 1994

Fingerprint

Fatty Acid Synthases
Antineoplastic Agents
Fatty Acids
Cerulenin
NADP
Malonyl Coenzyme A
Glycerides
Palmitates
Breast Neoplasms
Neoplasms
Therapeutics
Growth
Stearates
Peptides
Acetyl Coenzyme A
Myristic Acid
Sequence Homology
Dimethyl Sulfoxide
Tumor Cell Line
Acetates

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Kuhajda, F. P., Jenner, K., Wood, F. D., Hennigar, R. A., Jacobs, L. B., Dick, J. D., & Pasternack, G. R. (1994). Fatty acid synthesis: A potential selective target for antineoplastic therapy. Proceedings of the National Academy of Sciences of the United States of America, 91(14), 6379-6383. https://doi.org/10.1073/pnas.91.14.6379

Fatty acid synthesis : A potential selective target for antineoplastic therapy. / Kuhajda, Francis P.; Jenner, Kris; Wood, Fawn D.; Hennigar, Randolph A.; Jacobs, Lisa B.; Dick, James D.; Pasternack, Gary R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 91, No. 14, 05.07.1994, p. 6379-6383.

Research output: Contribution to journalArticle

Kuhajda, FP, Jenner, K, Wood, FD, Hennigar, RA, Jacobs, LB, Dick, JD & Pasternack, GR 1994, 'Fatty acid synthesis: A potential selective target for antineoplastic therapy', Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 14, pp. 6379-6383. https://doi.org/10.1073/pnas.91.14.6379
Kuhajda, Francis P. ; Jenner, Kris ; Wood, Fawn D. ; Hennigar, Randolph A. ; Jacobs, Lisa B. ; Dick, James D. ; Pasternack, Gary R. / Fatty acid synthesis : A potential selective target for antineoplastic therapy. In: Proceedings of the National Academy of Sciences of the United States of America. 1994 ; Vol. 91, No. 14. pp. 6379-6383.
@article{834ebdaf9c5147adb1217c6b618f8fbd,
title = "Fatty acid synthesis: A potential selective target for antineoplastic therapy",
abstract = "OA-519 is a prognostic molecule found in tumor cells from breast cancer patients with markedly worsened prognosis. We purified OA-519 from human breast carcinoma cells, obtained its peptide sequence, and unambiguously identified it as fatty acid synthase through sequence homology and enzymology. Tumor fatty acid synthase is an ≃270-kDa polypeptide which specifically abolished immunostaining of human breast cancers by anti-OA-519 antibodies. Tumor fatty acid synthase oxidized NADPH in a malonyl-CoA- dependent fashion and synthesized fatty acids composed of 80{\%} palmitate, 10{\%} myristate, and 10{\%} stearate from acetyl-CoA, malonyl-CoA, and NADPH with a specific activity of 624 nmol of NADPH oxidized per min per mg. Tumor cell lines with elevated fatty acid synthase showed commensurate increases in incorporation of [U-14C]acetate into acylglycerols demonstrating that fatty acid synthase increases occur in the context of overall increases in endogenous fatty acid synthesis. Cerulenin inhibited acylglycerol synthesis in tumor cells and fibroblast controls in a dose-dependent fashion and also caused a growth inhibition which generally paralleled the level of endogenous fatty acid synthesis. Supraphysiologic levels of palmitate, 14 μM in dimethyl sulfoxide, significantly reversed the growth inhibition caused by cerulenin at concentrations of up to 5 μg/ml, indicating that cerulenin- mediated growth inhibition was due to fatty acid synthase inhibition.",
author = "Kuhajda, {Francis P.} and Kris Jenner and Wood, {Fawn D.} and Hennigar, {Randolph A.} and Jacobs, {Lisa B.} and Dick, {James D.} and Pasternack, {Gary R.}",
year = "1994",
month = "7",
day = "5",
doi = "10.1073/pnas.91.14.6379",
language = "English (US)",
volume = "91",
pages = "6379--6383",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "14",

}

TY - JOUR

T1 - Fatty acid synthesis

T2 - A potential selective target for antineoplastic therapy

AU - Kuhajda, Francis P.

AU - Jenner, Kris

AU - Wood, Fawn D.

AU - Hennigar, Randolph A.

AU - Jacobs, Lisa B.

AU - Dick, James D.

AU - Pasternack, Gary R.

PY - 1994/7/5

Y1 - 1994/7/5

N2 - OA-519 is a prognostic molecule found in tumor cells from breast cancer patients with markedly worsened prognosis. We purified OA-519 from human breast carcinoma cells, obtained its peptide sequence, and unambiguously identified it as fatty acid synthase through sequence homology and enzymology. Tumor fatty acid synthase is an ≃270-kDa polypeptide which specifically abolished immunostaining of human breast cancers by anti-OA-519 antibodies. Tumor fatty acid synthase oxidized NADPH in a malonyl-CoA- dependent fashion and synthesized fatty acids composed of 80% palmitate, 10% myristate, and 10% stearate from acetyl-CoA, malonyl-CoA, and NADPH with a specific activity of 624 nmol of NADPH oxidized per min per mg. Tumor cell lines with elevated fatty acid synthase showed commensurate increases in incorporation of [U-14C]acetate into acylglycerols demonstrating that fatty acid synthase increases occur in the context of overall increases in endogenous fatty acid synthesis. Cerulenin inhibited acylglycerol synthesis in tumor cells and fibroblast controls in a dose-dependent fashion and also caused a growth inhibition which generally paralleled the level of endogenous fatty acid synthesis. Supraphysiologic levels of palmitate, 14 μM in dimethyl sulfoxide, significantly reversed the growth inhibition caused by cerulenin at concentrations of up to 5 μg/ml, indicating that cerulenin- mediated growth inhibition was due to fatty acid synthase inhibition.

AB - OA-519 is a prognostic molecule found in tumor cells from breast cancer patients with markedly worsened prognosis. We purified OA-519 from human breast carcinoma cells, obtained its peptide sequence, and unambiguously identified it as fatty acid synthase through sequence homology and enzymology. Tumor fatty acid synthase is an ≃270-kDa polypeptide which specifically abolished immunostaining of human breast cancers by anti-OA-519 antibodies. Tumor fatty acid synthase oxidized NADPH in a malonyl-CoA- dependent fashion and synthesized fatty acids composed of 80% palmitate, 10% myristate, and 10% stearate from acetyl-CoA, malonyl-CoA, and NADPH with a specific activity of 624 nmol of NADPH oxidized per min per mg. Tumor cell lines with elevated fatty acid synthase showed commensurate increases in incorporation of [U-14C]acetate into acylglycerols demonstrating that fatty acid synthase increases occur in the context of overall increases in endogenous fatty acid synthesis. Cerulenin inhibited acylglycerol synthesis in tumor cells and fibroblast controls in a dose-dependent fashion and also caused a growth inhibition which generally paralleled the level of endogenous fatty acid synthesis. Supraphysiologic levels of palmitate, 14 μM in dimethyl sulfoxide, significantly reversed the growth inhibition caused by cerulenin at concentrations of up to 5 μg/ml, indicating that cerulenin- mediated growth inhibition was due to fatty acid synthase inhibition.

UR - http://www.scopus.com/inward/record.url?scp=0028301959&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028301959&partnerID=8YFLogxK

U2 - 10.1073/pnas.91.14.6379

DO - 10.1073/pnas.91.14.6379

M3 - Article

VL - 91

SP - 6379

EP - 6383

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 14

ER -