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.

doi:10.1073/pnas.91.14.6379

Cited by 608 publications

(474 citation statements)

References 24 publications

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“…Fatty acid synthase (FAS), the main enzyme involved in de novo fatty acid synthesis, is coordinately regulated at the transcriptional level together with other lipogenic genes to provide balanced amounts of lipids for membrane biosynthesis [7,13]. FAS concentration is very low in non-cancerous cells, while it is overexpressed in a wide variety of human cancer cells, supporting the synthesis of phospholipids required for the newly synthesized cellular membrane [31]. Although the ultimate mechanisms responsible for tumor-associated FAS overexpression are not completely understood, growth factor and hormone transduction pathways have been indicated as major contributors.…”

Section: Discussionmentioning

confidence: 99%

SLC37A1 Gene expression is up-regulated by epidermal growth factor in breast cancer cells

Iacopetta

Lappano

Cappello

et al. 2009

Breast Cancer Res Treat

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Phospholipid biosynthesis exerts an important role in the proliferation of tumor cells; however, the regulation of the proteins involved in this context still remains to be fully evaluated. SLC37A1 protein belongs to a small family of sugar-phosphate/phosphate exchangers. The sequence homology with the bacterial glycerol-3-phosphate transporter (30%) suggests that SLC37A1 might be able to catalyze an exchange of glycerol-3-phosphate against phosphate. Glycerol-3-phosphate, found in different cellular compartments, is a fundamental substrate in phospholipid biosynthesis. In the present study, we demonstrate for the first time that epidermal growth factor (EGF) transactivates SLC37A1 promoter sequence and induces SLC37A1 mRNA, and protein expression through the EGFR/MAPK/ Fos transduction pathway in ER-negative SkBr3 breast cancer cells. These findings were corroborated by comparable results obtained in ER-positive endometrial Ishikawa tumor cells. Interestingly, we also show that SLC37A1 protein localizes in the endoplasmic reticulum, hence supporting its possible involvement in phospholipid biosynthesis. On the basis of our data, the up-regulation of SLC37A1 gene expression should be included among the well-known stimulatory action exerted by EGF in breast cancer cells. In addition, further studies are required to provide evidence concerning the potential role of EGFmediated SLC37A1 induction in breast tumor cells.

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Section: Discussionmentioning

confidence: 99%

SLC37A1 Gene expression is up-regulated by epidermal growth factor in breast cancer cells

Iacopetta

Lappano

Cappello

et al. 2009

Breast Cancer Res Treat

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“…21 The majority of human cancers, including cancer of the breast, colon, ovary, lung and prostate express elevated levels of FAS. 4 Inhibition of FAS activity inhibits tumor cell growth and induces apoptosis 15 rendering FAS an important target for anticancer drug development.…”

Section: Discussionmentioning

confidence: 99%

Suppression of fatty acid synthase in MCF-7 breast cancer cells by tea and tea polyphenols: a possible mechanism for their hypolipidemic effects

et al. 2003

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Tea is a heavily consumed beverage world wide because of its unique aroma, less cost and broad availability. Fatty acid synthase (FAS) is a key enzyme in lipogenesis. FAS is overexpressed in the malignant human breast carcinoma MCF-7 cells and its expression is further enhanced by the epidermal growth factor (EGF). The EGF-induced expression of FAS was inhibited by green and black tea extracts. The expression of FAS was also suppressed by the tea polyphenol (À)-epigallocatechin 3-gallate (EGCG), theaflavin (TF-1), TF-2 and theaflavin 3,3 0 -digallate(TF-3) at both protein and mRNA levels that may lead to the inhibition of cell lipogenesis and proliferation. Both EGCG and TF-3 inhibit the activation of Akt and block the binding of Sp-1 to its target site. Furthermore, the EGF-induced biosyntheses of lipids and cell proliferation were significantly suppressed by EGCG and TF-3. These findings suggest that tea polyphenols suppress FAS expression by downregulating EGF receptor/ PI3K/Akt/Sp-1 signal transduction pathway, and tea and tea polyphenols might induce hypolipidemic and antiproliferative effects by suppressing FAS.

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“…The endogenously synthesized fatty acids in cancer cells are predominantly utilized for structural lipids, such as membrane phospholipids rather than for energy storage as triglycerides. 42 As a result of brisk lipogenesis, the high steady-state levels of malonyl-CoA inhibit carnitine palmitoyltransferase-1, which transports long-chain acyl-CoAs into the mitochondria for oxidation, thus preventing a futile cycle of lipogenesis and subsequent fatty acid oxidation. Thus, Akt activation induces an array of anabolic processes including aerobic glycolysis, increased lipogenesis, nucleic acid synthesis and protein synthesis with reduced fatty acid oxidation.…”

Section: Ampk Activation In Cancer Cellsmentioning

confidence: 99%

AMP-activated protein kinase and human cancer: cancer metabolism revisited

Kuhajda

2008

Int J Obes

Self Cite

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AMP-activated protein kinase (AMPK) and its upstream kinase, LKB1, act to both monitor and restore cellular energy in response to energy depletion. Studied extensively in liver and skeletal muscle, AMPK is phosphorylated and activated by LKB1 in response to increasing AMP/ATP ratios, which occur in a variety of settings including hypoxia, nutrient starvation and redox imbalance. Interest in the roles of both AMPK and LKB1 in cancer has grown substantially, following the identification of LKB1 as the tumor suppressor gene mutated in the Peutz-Jegher familial cancer syndrome. Patients with the Peutz-Jegher syndrome harbor a single inactive LKB1 gene, and acquisition of a second inactivating lesion (loss of heterozygosity) leads to the development of the cancer in a variety of organs. Thus, the loss of AMPK activation is hypothesized to promote the development of malignancy. Conversely, pharmacological AMPK activation has recently been shown to be cytotoxic to many established human cancer cell lines in vitro and in human cancer xenograft and mouse cancer allografts. Previously, changes in cell metabolism that accompanied the malignant phenotype have largely been considered a consequence of cellular transformation. Now, AMPK and energy metabolism are linked to the development and maintenance of the malignant phenotype. These findings have led to renewed interest in AMPK and cancer cell metabolism in general as potential targets for cancer therapy.

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Fatty acid synthesis: a potential selective target for antineoplastic therapy.

Cited by 608 publications

References 24 publications

SLC37A1 Gene expression is up-regulated by epidermal growth factor in breast cancer cells

SLC37A1 Gene expression is up-regulated by epidermal growth factor in breast cancer cells

Suppression of fatty acid synthase in MCF-7 breast cancer cells by tea and tea polyphenols: a possible mechanism for their hypolipidemic effects

AMP-activated protein kinase and human cancer: cancer metabolism revisited

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