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Fatty Acid Synthase (FAS), Vitamin D, and Cancer

Also see:
Excess Dietary Phosphorus Lowers Vitamin D Levels
Calcium Paradox
Calcium to Phosphorus Ratio, PTH, and Bone Health
Dairy, Calcium, and Weight Management in Adults and Children
PUFA, Ketones, and Sugar Restriction Promote Tumor Growth
Novel compound shows promise against breast cancer

“”Cancer metabolism” or stress metabolism typically involves an excess of the adaptive hormones, resulting from an imbalance of the demands made on the organism and the resources available to the organism. Excessive stimulation depletes glucose and produces lactic acid, and causes cortisol to increase, causing a shift to the consumption of fat and protein rather than glucose. Increased cortisol activates the Randle effect (the inhibition of glucose oxidation by free fatty acids), accelerates the breakdown of protein into amino acids, and activates the enzyme fatty acid synthase, which produces fatty acids from amino acids and pyruvate, to be oxidized in a “futile cycle,” producing heat, and increasing the liberation of ammonia from the amino acids. Ammonia suppresses respiratory, and stimulates glycolytic, activity.” -Ray Peat, PhD

“There are many people currently recommending fish oil (or other highly unsaturated oils) for preventing or treating cancer, and it has become almost as common to recommend a sugar free diet, “because sugar feeds cancer.” This is often, incorrectly, said to be the meaning of Warburg’s demonstration that cancer cells have a respiratory defect that causes them to produce lactic acid from glucose even in the presence of oxygen. Cancer cells use glucose and the amino acid glutamine primarily for synthetic purposes, and use fats as their energy source;the growth stimulating effect of the “essential fatty acids” (Sueyoshi and Nagao, 1962a; Holley, et al., 1974) shows that depriving a tumor of those fats retards its growth. The great energetic inefficiency of the cancer metabolism, which causes it to produce a large amount of heat and to cause systemic stress, failure of immunity, and weight loss, is because it synthesizes fat from glucose and amino acids, and then oxidizes the fat as if it were diabetic.” -Ray Peat, PhD

“When the system is disturbed by chronic hyperglycemia and an inability to use glucose, a sort of equilibrium will be restored by the production of a tumor that pumps glucose out of the system. Although tumors consume sugar and release lactic acid, they are doing something very odd: They convert a large amount of glucose into fat, and then oxidize that fat. The enzyme system, fatty acid synthase (FAS), is an effective way to dispose of glucose because its energetic inefficiency.” -Ray Peat, PhD

Nutrition. 2000 Mar;16(3):202-8.
Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology.
Kuhajda FP.
This review documents the changing perspectives on the function of fatty-acid synthase and fatty-acid synthesis in human tumor biology. With the recent discovery that human cancer cells express high levels of fatty-acid synthase and undergo significant endogenous fatty-acid synthesis, our understanding of the role of fatty acids in tumor biology is expanding. Once considered largely an anabolic-energy-storage pathway, fatty-acid synthesis is now associated with clinically aggressive tumor behavior and tumor-cell growth and survival and has become a novel target pathway for chemotherapy development. These findings will ultimately enhance our understanding of fatty acids in tumor biology and may provide new diagnostic and therapeutic moieties for patient care.

J Cell Biochem. 2004 Jan 1;91(1):47-53.
Fatty acid synthase: a metabolic oncogene in prostate cancer?
Baron A, Migita T, Tang D, Loda M.
In addition, tumors overexpressing fatty acid synthase (FAS), the enzyme responsible for de novo synthesis of fatty acids, display aggressive biologic behavior compared to those tumors with normal FAS levels, suggesting that FAS overexpression confers a selective growth advantage. Here, we will review the roles that FAS plays in important cellular processes such as apoptosis and proliferation. In addition, speculations on the putative role of FAS in the altered metabolic pathways of prostate cancer cells will be explored.Because of the frequent overexpression of this enzyme prostate cancer, FAS constitutes a therapeutic target in this disease.

Oncogene. 2005 Aug 11;24(34):5389-95.
FAS expression inversely correlates with PTEN level in prostate cancer and a PI 3-kinase inhibitor synergizes with FAS siRNA to induce apoptosis.
Bandyopadhyay S, Pai SK, Watabe M, Gross SC, Hirota S, Hosobe S, Tsukada T, Miura K, Saito K, Markwell SJ, Wang Y, Huggenvik J, Pauza ME, Iiizumi M, Watabe K.
Fatty acid synthase (FAS), a key enzyme of the fatty acid biosynthetic pathway, has been shown to be overexpressed in various types of human cancer and is, therefore, considered to be an attractive target for anticancer therapy. However, the exact mechanism of overexpression of the FAS gene in tumor cells is not well understood. In this report, we demonstrate that the expression of the tumor suppressor gene PTEN has a significant inverse correlation with FAS expression in the case of prostate cancer in the clinical setting, and inhibition of the PTEN gene leads to the overexpression of FAS in vitro. We also found that the combination of the expression status of these two genes is a better prognostic marker than either gene alone. Furthermore, our results indicate that the specific inhibition of FAS gene by siRNA leads to apoptosis of prostate tumor cells, and inhibition of PI 3-kinase pathway synergizes with FAS siRNA to enhance tumor cell death. These results provide a strong rationale for exploring the therapeutic use of an inhibitor of the PTEN signaling pathway in conjunction with the FAS siRNA to inhibit prostate tumor growth.

“When PTH is kept low, cells increase their formation of the uncoupling proteins, that cause mitochondria to use energy at a higher rate, and this is associated with decreased activity of the fatty acid synthase enzymes…Cancer involves increased activity of the fatty acid synthase enzymes. Increased calcium consumption beneficially affects both sets of enzymes, uncoupling proteins and fatty acid synthase.” -Ray Peat, PhD

“One of the reasons a lot of people give, if they have overcome the idea that milk forms mucous, or is a risk for diseases and so on; one of their arguments is that it makes them fat. But, all the research on animals, and as far as it goes, human research, shows that milk is probably the best reducing foods there is. The mechanisms for that are now known. Not only the anti-stress effects of casein, and a good balance of saturated fats and so on, but the calcium alone is very important metabolic regulator, that it happens to inhibit the fat-forming enzymes fatty acid synthase, and incidentally that’s a characteristic enzyme that goes wild in cancer. But calcium and milk inhibit that fatty acid synthase, reducing the formation of fats and at the same time it activates the uncoupling proteins in the mitochondria, which are associated with increased longevity. Because they, by increasing the metabolic rate, the uncoupling proteins burn calories faster but they protect against free-radical oxidation. That they pull the fuel through the oxidation process so fast in effect, that none of it goes astray in random oxidation, where if you inhibit your energy producing enzymes you tend to get random, stray oxidation that damage the mitochondria. So the uncoupling proteins burn calories faster, at the same time that your reducing fat synthesis and milk is, as far as I know, they only food does both of those things simultaneously” -Ray Peat, PhD

Ann Diagn Pathol. 2002 Aug;6(4):229-35.
P53 as a marker of differentiation between hyperplastic and adenomatous parathyroids.
Ricci F, Mingazzini PL, Sebastiani V, D’Erasmo E, Letizia C, De Toma G, Alò PL.
Primary hyperparathyroidism is the clinical result of parathyroid adenoma or hyperplasia, rarely of carcinoma. Clinical, serologic, and radiologic data are unable to discriminate a single parathyroid adenoma from an enlarged hyperplastic gland. Morphologic features also overlap in adenoma and small hyperplastic gland. Studying immunohistochemical expression of fatty acid synthase (FAS), p53, Ki67 and bcl-2, we found that among 21 adenomas 19 (90.5%) were positive for FAS, 12 (57.2%) for Ki67, 11 (52.4%) for p53, and 16 (76.2%) for bcl-2; among 12 hyperplasias, 12 (100%) were positive for FAS, 6 (50%) for KI67, 8 (66.7%) for p53, and 8 (66.7%) for bcl-2. Statistical analysis showed that FAS was associated with parathormone (PTH) (P =.001), Ki67 (P =.01), and p53 (P =.01). Moreover, FAS was associated with hyperplastic (P =.0001) and adenomatous glands (P =.0001). Ki67 was associated with both adenomatous (P =.02) and hyperplastic glands (P =.005). P53 protein were associated only with hyperplastic glands (P =.01). The different occurrence of p53 in parathyroids adenoma and hyperplasia may enable a different management and follow-up of the patients with primary hyperparathyroidism, stratifing them into two groups. The first, with a “false” adenoma having a high risk of relapse, may necessitate exams like serum calcium levels, PTH concentrations, urinary calcium levels for 24 hours, kidney functional tests, and radiology and ultrasound every 3 to 6 months, whereas the second with “true” adenoma, at low risk of relapse, may be checked less frequently with serum calcium levels and PTH concentrations.

Ann Diagn Pathol. 1999 Oct;3(5):287-93.
Immunohistochemical study of fatty acid synthase, Ki67, proliferating cell nuclear antigen, and p53 expression in hyperplastic parathyroids.
Alò PL, Visca P, Mazzaferro S, Serpieri DE, Mangoni A, Botti C, Monaco S, Carboni M, Zaraca F, Trombetta G, Di Tondo U.
Patients with secondary hyperparathyroidism following chronic renal disease frequently develop hyperplastic parathyroids. Hyperplastic parathyroids have an increased number of chief cells, a decreased amount of stromal fat, and a nodular or diffuse histologic pattern. Hyperplastic parathyroids may also express higher proliferative activity compared with controls. We evaluated the morphologic features and immunohistochemical expression of fatty acid synthase (FAS), Ki67, proliferating cell nuclear antigen, and p53 protein in 78 hyperplastic parathyroids from 20 patients with secondary hyperparathyroidism. Twenty normal parathyroids incidentally removed during nonneoplastic thyroid surgery were used as controls. Our results showed that hyperplastic glands overexpress FAS (P =.06). Statistical analysis also revealed a significant association between FAS and p53 protein (P =.006) and between FAS and hyperplastic glands with a predominant nodular pattern (P =.02). Hyperplastic parathyroids from patients with chronic renal failure strongly express FAS. Fatty acid synthase may therefore be a potential biological indicator of highly proliferating parathyroid cells.

The FASEB Journal. 2000;14:1132-1138.
Regulation of adiposity by dietary calcium
MICHAEL B. ZEMEL*1, HANG SHI*, BETTY GREER*, DOUGLAS DIRIENZO† and PAULA C. ZEMEL*
Recent data from this laboratory demonstrate that increasing adipocyte intracellular Ca2+ results in a coordinated stimulation of lipogenesis and inhibition of lipolysis. We have also noted that increasing dietary calcium of obese patients for 1 year resulted in a 4.9 kg loss of body fat (P<0.01). Accordingly, we tested the possibility that calcitrophic hormones may act on adipocytes to increase Ca2+ and lipid metabolism by measuring the effects of 1,25-(OH)2-D in primary cultures of human adipocytes, and found significant, sustained increases in intracellular Ca2+ and a corresponding marked inhibition of lipolysis (EC50 ~50 pM; P<0.001), suggesting that dietary calcium could reduce adipocyte mass by suppressing 1,25-(OH)2-D. To test this hypothesis, we placed transgenic mice expressing the agouti gene specifically in adipocytes on a low (0.4%) Ca/high fat/high sucrose diet either unsupplemented or with 25 or 50% of the protein replaced by non-fat dry milk or supplemented to 1.2% Ca with CaCO3 for 6 wk. Weight gain and fat pad mass were reduced by 26–39% by the three high calcium diets (P<0.001). The high calcium diets exerted a corresponding 51% inhibition of adipocyte fatty acid synthase expression and activity (P<0.002) and stimulation of lipolysis by 3.4- to 5.2-fold (P<0.015). This concept of calcium modulation of adiposity was further evaluated epidemiologically in the NHANES III data set. After controlling for energy intake, relative risk of being in the highest quartile of body fat was set to 1.00 for the lowest quartile of Ca intake and was reduced to 0.75, 0.40, and 0.16 for the second, third, and fourth quartiles, respectively, of calcium intake for women (n=380;P<0.0009); a similar inverse relationship was also noted in men (n=7114; P<0.0006). Thus, increasing dietary calcium suppresses adipocyte intracellular Ca2+ and thereby modulates energy metabolism and attenuates obesity risk.

Clin Cancer Res. 2003 Jun;9(6):2204-12.
Expression of fatty acid synthase as a prognostic indicator in soft tissue sarcomas.
Takahiro T, Shinichi K, Toshimitsu S.
PURPOSE: Fatty acid synthase (FAS) is a key enzyme in the de novo biosynthesis of fatty acids. Carcinoma cells are dependent on endogenous fatty acid synthesis for growth in vitro. In a subset of human cancers, elevated FAS is associated with poor prognosis; however, the expression of FAS and the relationship between FAS and prognosis in soft tissue sarcomas (STSs) have not been studied. The objective of this study is to examine the expression of FAS in STSs and determine its relationship to clinicopathological features and prognosis. EXPERIMENTAL DESIGN: Sixty-four cases of STS were examined. The clinicopathological features and immunohistochemical expression of FAS and Ki-67 antigen were studied. Survival analysis was performed using the log-rank test and the Cox multivariate regression model. RESULTS: FAS expression was observed in 20 of 64 cases (31.3%) of STS. FAS-positive sarcomas were found in 13 of 23 malignant fibrous histiocytomas, 3 of 17 liposarcomas, 3 of 7 malignant peripheral nerve sheath tumors, and 1 extraskeletal mesenchymal chondrosarcoma. No expression of FAS was seen in the synovial sarcomas, leiomyosarcomas, or rhabdomyosarcomas that were examined. Clinicopathologically, FAS-positive tumors were significantly deep-seated (P = 0.02) and large in size (P = 0.03). FAS expression correlated with decreased disease-free survival (P = 0.006) and decreased overall survival (P = 0.003). In a multivariate analysis, expression of FAS was able to predict decreased disease-free survival but did not reach the level of significance for overall survival.
CONCLUSIONS: FAS expression is one of the predictive indicators for disease prognosis in STS.

The enzyme, fatty acid synthase (FAS), normally active in the liver and fat cells and in the estrogen-stimulated uterus, is highly active in cancers, and its activity is an inverse indicator of prognosis. Inhibiting it can cause cancer cells to die, so the pharmaceutical industry is looking for drugs that can safely inhibit it. This enzyme is closely associated with the rate of cell proliferation, and its activity is increased by both cortisol and estrogen. -Ray Peat, PhD

Int J Gynecol Pathol. 1997 Jan;16(1):45-51.
Expression of fatty acid synthase is closely linked to proliferation and stromal decidualization in cycling endometrium.
Pizer ES, Kurman RJ, Pasternack GR, Kuhajda FP.
Estrogen-driven proliferative phase growth is the most rapid physiological proliferative process that occurs in the adult. The tissue growth that occurs during this phase of the menstrual cycle requires incorporation of a substantial quantity of fatty acid into the structural lipids of cell membranes. Fatty acid synthase (FAS) is the major biosynthetic enzyme required for de novo synthesis of fatty acids. In this immunohistochemical study, we have observed that human endometrium displays distinct patterns of FAS expression in the proliferative and secretory phases of the normal menstrual cycle. Proliferative endometrial glands and stroma show high FAS expression that closely correlates with expression of Ki-67, estrogen and progesterone receptors, supporting the view that FAS expression plays a role in cellular proliferation in response to estrogen. FAS expression declines during early to midsecretory phase, then reappears in decidualized stromal cells in late secretory phase as well as in the decidua of pregnancy. The second wave of FAS expression correlates with progesterone-receptor localization in the decidual cells, a finding suggesting a second induction of FAS expression in the endometrium, associated with differentiation, that may be regulated by progesterone.

Anti-estrogen Effect and Inhibition of FAS by Vitamin D
J Steroid Biochem Mol Biol. 2003 May;85(1):1-8.
Inhibition of fatty acid synthase expression by 1alpha,25-dihydroxyvitamin D3 in prostate cancer cells. Qiao S, Pennanen P, Nazarova N, Lou YR, Tuohimaa P.
1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) and its derivatives are a potential treatment of human prostate cancer. The antiproliferative action of 1alpha,25(OH)(2)D(3) is mainly exerted through nuclear vitamin D receptor (VDR)-mediated control of target gene transcription. To explore the target genes which are regulated by 1alpha,25(OH)(2)D(3) in human prostate cancer LNCaP cells, cDNA microarray was performed by using a chip that contains 3000 gene probes. The results showed that 24 genes were regulated by 1alpha,25(OH)(2)D(3). Five of them encode proteins which belong to metabolic enzymes and fatty acid biosynthesis. Fatty acid synthase (FAS) was found to be down-regulated by 1alpha,25(OH)(2)D(3), and the regulation was confirmed by real-time quantitative RT-PCR analysis. Inhibition of FAS expression by 1alpha,25(OH)(2)D(3) in LNCaP cells was more than 50% at 6h. Inhibitory effect of 1alpha,25(OH)(2)D(3) on FAS expression was completely blocked in the presence of protein synthesis inhibitor cycloheximide, indicating that the down-regulation of FAS gene expression by 1alpha,25(OH)(2)D(3) was indirect in LNCaP cells. An inhibition of FAS activity by cerulenin resulted in a strong inhibition of LNCaP cell proliferation. The inhibition of FAS expression and cell proliferation by 1alpha,25(OH)(2)D(3) seemed to be androgen-dependent, since antiandrogen, casodex and DCC-treatment of serum blocked the vitamin D action. The findings suggest that FAS is involved in the antiproliferative effect of 1alpha,25(OH)(2)D(3) in presence of androgens on prostate cancer LNCaP cells. J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):343-8.

Epub 2010 Feb 13.
Vitamin D and breast cancer: inhibition of estrogen synthesis and signaling.
Krishnan AV, Swami S, Feldman D.
Calcitriol (1,25-dihydroxyvitamin D3), the hormonally active metabolite of vitamin D, inhibits the growth and induces the differentiation of many malignant cells including breast cancer (BCa) cells. Calcitriol exerts its anti-proliferative activity in BCa cells by inducing cell cycle arrest and stimulating apoptosis. Calcitriol also inhibits invasion, metastasis and tumor angiogenesis in experimental models of BCa. Our recent studies show additional newly discovered pathways of calcitriol action to inhibit the growth of BCa cells. Calcitriol suppresses COX-2 expression and increases that of 15-PGDH thereby reducing the levels and biological activity of prostaglandins (PGs). Calcitriol decreases the expression of aromatase, the enzyme that catalyzes estrogen synthesis selectively in BCa cells and the breast adipose tissue surrounding BCa, by a direct repression of aromatase transcription via promoter II as well as an indirect effect due to the reduction in the levels and biological activity of PGE2, which is a major stimulator of aromatase transcription through promoter II in BCa. Calcitriol down-regulates the expression of estrogen receptor alpha and thereby attenuates estrogen signaling in BCa cells including the proliferative stimulus provided by estrogens. We hypothesize that the inhibition of estrogen synthesis and signaling by calcitriol and its anti-inflammatory actions will play an important role in the use of calcitriol for the prevention and/or treatment of BCa.

Cancer Res. 1994 Mar 15;54(6):1458-64.
Antiestrogenic effects of all-trans-retinoic acid and 1,25-dihydroxyvitamin D3 in breast cancer cells occur at the estrogen response element level but through different molecular mechanisms.
Demirpence E, Balaguer P, Trousse F, Nicolas JC, Pons M, Gagne D.
Most breast tumors show estrogen-dependent growth and are thus susceptible to antiestrogenic therapy. MCF-7 cells, obtained from a human estrogen-dependent breast carcinoma, are widely used for studying the modulation of estrogenic responses by different effectors. All-trans-retinoic acid (RA) and 1,25-dihydroxyvitamin D3 (Vit D3) inhibited estrogen-induced growth of MCF-7 cells and their effect was potentiated by the classical antiestrogen, hydroxytamoxifen. In MCF-7 cells, we found that RA and Vit D3 also inhibited estrogen-induced transcription; this was shown both for an endogenous gene (pS2) and for various exogenous transfected genes. Their inhibitory effect could not be reversed by increasing estradiol concentrations, showing that contrary to classical antiestrogens, they did not compete with estradiol to bind the estrogen receptor (ER). Analysis of the inhibitory mechanisms indicates that RA and Vit D3 receptors can directly or indirectly impair the binding of ER to the estrogen responsive element. The antagonist effect of RA would be found especially at DNA level since it seems to essentially involve an estrogen responsive element. The antagonist effect of Vit D3 would be found especially at the ER level since it seems to concern estrogen binding and dimerization domains of ER. We conclude that the antiestrogenic effects of RA and Vit D3 are similar since they can, via their receptors, interfere with estrogenic action at the estrogen responsive element level but that they are not identical since different molecular mechanisms are involved.

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