Increased fatty acid synthase as a therapeutic target in androgen-independent prostate cancer progression

Ellen S. Pizer, Beth Pflug, G. Steven Bova, Wan Fang Han, Michael S. Udan, Joel B. Nelson

Research output: Contribution to journalArticle

131 Citations (Scopus)

Abstract

BACKGROUND. Fatty acid synthase (FAS) performs the anabolic conversion of dietary carbohydrate or protein to fat. FAS expression is low in most normal tissues, but is elevated in many human cancers, including androgen-sensitive and androgen-independent prostate cancer. METHODS. Immunohistochemical evaluation of FAS expression was performed in human prostate cancer specimens under various states of androgen ablation. In vitro and in vivo prostate cancer models were evaluated for FAS expression and activity under androgenic and androgen-depleted conditions, and were tested for sensitivity to antimetabolite drugs that target fatty acid synthesis. RESULTS. While FAS expression in the prostate was androgen responsive, it persisted or was reactivated in human prostate carcinoma after androgen ablation, and was high in 82% of lethal tumors examined at autopsy. Similar patterns of FAS expression and fatty acid synthesis were seen in cell culture and xenograft models of human prostate cancer. Pharmacologic inhibition of FAS resulted in a dose-dependent reduction of tumor growth in these models, including fourfold inhibition of an androgen-independent human prostate cancer xenograft with little associated toxicity. CONCLUSIONS. The data suggest that FAS expression/FA synthesis provides an important functional aspect of the malignant phenotype in prostate cancer, perhaps supporting cell growth or survival. FAS expression may be upregulated by alternate signaling pathways important for prostate cancer growth under androgen withdrawal. The re-emergence of FAS expression and activity during the development of androgen independence demonstrate that FAS may serve as a novel target for antimetabolite therapy in prostate cancer.

Original languageEnglish (US)
Pages (from-to)102-110
Number of pages9
JournalProstate
Volume47
Issue number2
DOIs
StatePublished - May 1 2001
Externally publishedYes

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Fatty Acid Synthases
Androgens
Prostatic Neoplasms
Therapeutics
Antimetabolites
Heterografts
Prostate
Fatty Acids
Growth
Dietary Carbohydrates
Neoplasms
Dietary Proteins
Autopsy
Cell Culture Techniques
Fats

Keywords

  • Androgen
  • Chemotherapy
  • Fatty acid synthase
  • Prostate cancer
  • Tumor progression

ASJC Scopus subject areas

  • Urology

Cite this

Increased fatty acid synthase as a therapeutic target in androgen-independent prostate cancer progression. / Pizer, Ellen S.; Pflug, Beth; Steven Bova, G.; Han, Wan Fang; Udan, Michael S.; Nelson, Joel B.

In: Prostate, Vol. 47, No. 2, 01.05.2001, p. 102-110.

Research output: Contribution to journalArticle

Pizer, Ellen S. ; Pflug, Beth ; Steven Bova, G. ; Han, Wan Fang ; Udan, Michael S. ; Nelson, Joel B. / Increased fatty acid synthase as a therapeutic target in androgen-independent prostate cancer progression. In: Prostate. 2001 ; Vol. 47, No. 2. pp. 102-110.
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abstract = "BACKGROUND. Fatty acid synthase (FAS) performs the anabolic conversion of dietary carbohydrate or protein to fat. FAS expression is low in most normal tissues, but is elevated in many human cancers, including androgen-sensitive and androgen-independent prostate cancer. METHODS. Immunohistochemical evaluation of FAS expression was performed in human prostate cancer specimens under various states of androgen ablation. In vitro and in vivo prostate cancer models were evaluated for FAS expression and activity under androgenic and androgen-depleted conditions, and were tested for sensitivity to antimetabolite drugs that target fatty acid synthesis. RESULTS. While FAS expression in the prostate was androgen responsive, it persisted or was reactivated in human prostate carcinoma after androgen ablation, and was high in 82{\%} of lethal tumors examined at autopsy. Similar patterns of FAS expression and fatty acid synthesis were seen in cell culture and xenograft models of human prostate cancer. Pharmacologic inhibition of FAS resulted in a dose-dependent reduction of tumor growth in these models, including fourfold inhibition of an androgen-independent human prostate cancer xenograft with little associated toxicity. CONCLUSIONS. The data suggest that FAS expression/FA synthesis provides an important functional aspect of the malignant phenotype in prostate cancer, perhaps supporting cell growth or survival. FAS expression may be upregulated by alternate signaling pathways important for prostate cancer growth under androgen withdrawal. The re-emergence of FAS expression and activity during the development of androgen independence demonstrate that FAS may serve as a novel target for antimetabolite therapy in prostate cancer.",
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