The expression of fatty acid synthase (FASE) is an early event in the development and progression of squamous cell carcinoma of the lung

Piyathilake, Chandrika J.; Frost, Andra R.; Manne, Upender; Bell, Walter C.; Weiss, Heidi L.; Heimburger, Douglas C.; Grizzle, William E.

doi:10.1053/hupa.2000.9842

Cited by 134 publications

(102 citation statements)

References 17 publications

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“…Of interest, strong fatty acid synthase expression is noted in both congenital melanocytic nevus (f) and metastatic melanoma (l). (2), prostatic (3), colonic (4), ovarian (5), gastric (6), esophageal (7), pulmonary (8), oral (9), thyroid (10), mesothelial (11), endometrial (12), and melanocytic (13) origin. This information may possibly have therapeutic relevance because fatty acid synthase inhibitors, cerulenin and triclosan, have been shown to be cytotoxic to human cancer cells in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…1 Increased fatty acid synthase expression has been demonstrated in subsets of malignancies, including colon, breast, and ovarian carcinomas. [2][3][4][5][6][7][8][9][10][11][12] Recently, the expression of fatty acid synthase was shown to correlate with Breslow thickness in malignant melanoma while only weak expression was present in melanocytic nevi. 13 In addition, the expression of fatty acid synthase may have therapeutic relevance because fatty acid synthase inhibitors, cerulenin and triclosan, have been demonstrated to be cytotoxic to human cancer cells in vitro.…”

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confidence: 99%

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Fatty acid synthase expression in cutaneous melanocytic neoplasms

et al. 2005

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Mammalian fatty acid synthase is a multifunctional enzyme complex involved in de novo synthesis of saturated fatty acids, and inhibitors of fatty acid synthase are being evaluated as potential therapeutic agents. Increased fatty acid synthase expression has been demonstrated in subsets of malignancies, including colon, breast, endometrium, prostate and ovarian carcinomas, and recently malignant melanomas. We evaluated the immunohistochemical expression of fatty acid synthase in 155 cutaneous melanocytic lesions. They included 30 congenital nevi, 19 compound nevi, 40 Spitz nevi, 48 primary melanomas, and 18 metastatic melanomas. Fatty acid synthase expression was stronger in malignant melanomas in comparison to conventional nevi and Spitz nevi, and was the highest for metastatic melanoma. Of the primary malignant melanomas, mean fatty acid synthase scores were significantly greater for Clark levels IV and V compared to Clark levels I and II (Po0.001). In addition, melanomas with Breslow thickness 0.75-1.50 mm and 41.50 mm showed significantly higher mean fatty acid synthase scores compared with those with Breslow thickness o0.75 mm (P ¼ 0.013 and o0.001, respectively). Of interest, congenital melanocytic nevi also showed strong fatty acid synthase expression, similar to that seen in metastatic melanoma. This may represent persistence of or regression to a fetal phenotype since normal fetal tissues are known to express high levels of fatty acid synthase.

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Section: Discussionmentioning

confidence: 99%

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Fatty acid synthase expression in cutaneous melanocytic neoplasms

et al. 2005

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“…[16][17][18][19][20][21][22][23][24][25]28 Interestingly, FAS is already overexpressed in some noninvasive precursors, such as intraepithelial neoplasia of the squamous 24,25 or prostate 23 epithelium, intraductal mammary carcinoma, 20 or colorectal adenoma. [16][17][18] Thus, it seems to be an early event in carcinogenesis of these entities and resembles the early overexpression seen in our model.…”

Section: Discussionmentioning

confidence: 99%

“…11,12 Insulin is known to transcriptionally regulate FAS expression. [13][14][15] Several human neoplasms overexpress FAS, including colorectal, 16,17 endometrial, 18 gastric, 19 mammary, 20,21 ovary, 22 and prostate 23 adenocarcinomas, as well as oral 24 and pulmonary 25 squamous cell carcinomas, often associated with poor prognosis. 22,[26][27][28][29][30] Moreover, FAS inhibition triggered apoptosis in the MCF7 human breast cancer cell line.…”

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Overexpression of fatty acid synthase in chemically and hormonally induced hepatocarcinogenesis of the rat

Evert

Schneider‐Stock

Dombrowski

2005

Laboratory Investigation

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Fatty acid synthase (FAS) is the key enzyme of de novo fatty acid synthesis and has been shown to be involved in carcinogenesis of numerous human malignancies, including breast, colorectal, and prostate carcinomas, often associated with a worse prognosis. Although FAS is mainly expressed in the liver, an implication of FAS in hepatocarcinogenesis, has not yet been investigated. FAS expression is stimulated by insulin and glucose, and insulin is also the primary trigger of hepatocarcinogenesis in an endocrine experimental model, which is induced by low-number transplantation of islets of Langerhans into the livers of diabetic rats. We therefore investigated, whether FAS is implicated in hepatocarcinogenesis in this model and in comparison to chemically induced hepatocarcinogenesis after N-nitrosomorpholine (NNM) treatment in diabetic and normoglycemic rats. Preneoplastic clear-cell foci of altered hepatocytes (FAH), harvested after laser-microdissection of kryostat sections, showed an overexpression of FAS messenger RNA in gene expression profiles, done by arrayhybridization, and in quantitative RT-PCR (Light-Cycler). Virtually, all (96-98%) of the subsequently investigated FAH and the glycogenotic hepatocellular adenomas and carcinomas showed an additional strong FAS protein overexpression. In the NNM-model, FAS protein was also overexpressed in the vast majority (87%) of glycogenotic FAH and neoplasms, in particular in the diabetic animals. Also two spontaneous glycogenotic FAH in control animals displayed strong FAS overexpression. Basophilic lesions and neoplasms, which occasionally develop out of the primary clear-cell FAH at later stages of carcinogenesis, however, lost FAS overexpression. In conclusion, FAS overexpression is an early phenonemon in spontaneous, hormonally and chemically induced rat hepatocarcinogenesis, demonstrable in early clear-cell (glycogenotic) FAH and hepatocellular neoplasms. Keywords: fatty acid synthase; glucose; hepatocarcinogenesis; insulin; islet transplantatation; N-nitrosomorpholine After low-number transplantation of islets of Langerhans into the livers of diabetic rats, the liver acini draining the blood from the islet grafts show cellular alterations, the foci of altered hepatocytes (FAH). 1 FAH resemble the glycogen-storing or clear-cell phenotype of preneoplastic foci known from experimental and human hepatocarcinogenesis. 2,3 In the transplantation model, these preneoplastic FAH may develop into hepatocellular adenomas (HCA) and carcinomas (HCC) within 6-24 months after islet transplantation. 4 Previous results indicate that insulin is the primary trigger for the development of FAH and hepatocarcinogenesis in this model. 1,[4][5][6][7] In the beginning of the carcinogenic process, however, these FAH can be regarded as purely adaptative in nature. At this stage, insulin effects manifested in several aspects, that is, an increase in glycogen storage and proliferative activity, lipid accumulation, and altered expression of several insulinrelated proteins, including IGF-I a...

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“…Thus, FAS expression is generally low to undetectable in normal human tissues, other than the liver and adipose tissue. In contrast, FAS is overexpressed in many human tumours, including carcinoma of the breast (Milgraum et al, 1997;Wang et al, 2001b), prostate (Epstein et al, 1995;Swinnen et al, 2002), colon (Rashid et al, 1997), ovary (Gansler et al, 1997), endometrium (Pizer et al, 1998b), mesothelium (Gabrielson et al, 2001), lung (Piyathilake et al, 2000), thyroid (Vlad et al, 1999), and stomach (Kusakabe et al, 2002). Abnormally active endogenous fatty acid metabolism appears to be important for cancer cell proliferation and survival (Ookhtens et al, 1984).…”

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Fatty acid synthase: a novel target for antiglioma therapy

et al. 2006

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High levels of fatty acid synthase (FAS) expression have been observed in several cancers, including breast, prostate, colon and lung carcinoma, compared with their respective normal tissue. We present data that show high levels of FAS protein in human and rat glioma cell lines and human glioma tissue samples, as compared to normal rat astrocytes and normal human brain. Incubating glioma cells with the FAS inhibitor cerulenin decreased endogenous fatty acid synthesis by approximately 50%. Cell cycle analysis demonstrated a time-and dose-dependent increase in S-phase cell arrest following cerulenin treatment for 24 h. Further, treatment with cerulenin resulted in time-and dose-dependent decreases in glioma cell viability, as well as reduced clonogenic survival. Increased apoptotic cell death and PARP cleavage were observed in U251 and SNB-19 cells treated with cerulenin, which was independent of the death receptor pathway. Overexpressing Bcl-2 inhibited cerulenin-mediated cell death. In contrast, primary rat astrocytes appeared unaffected. Finally, RNAi-mediated knockdown of FAS leading to reduced FAS enzymatic activity was associated with decreased glioma cell viability. These findings suggest that FAS might be a novel target for antiglioma therapy.

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The expression of fatty acid synthase (FASE) is an early event in the development and progression of squamous cell carcinoma of the lung

Cited by 134 publications

References 17 publications

Fatty acid synthase expression in cutaneous melanocytic neoplasms

Fatty acid synthase expression in cutaneous melanocytic neoplasms

Overexpression of fatty acid synthase in chemically and hormonally induced hepatocarcinogenesis of the rat

Fatty acid synthase: a novel target for antiglioma therapy

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