Fatty acid synthase expression is increased in neoplastic lesions of the oral tongue

Krontiras, Helen; Roye, G. Dean; Beenken, Samuel E.; Myers, Richard S.; Mayo, Matthew S.; Peters, Glenn E.; Grizzle, William E.

doi:10.1002/(sici)1097-0347(199907)21:4<325::aid-hed6>3.0.co;2-p

Cited by 66 publications

(54 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The enzyme fatty acid synthase and its activity are highly elevated in biosynthetically altered anaplastic cells of poorly differentiated lesions as compared to moderate- and well-differentiated lesions. [23] However, in contrary to this statement, we observed the lowest level of VLDL, HDL, and TG in well differentiated lesions and the lowest level of LDL in moderately differentiated lesions. Therefore, the observations of this study do not support the hypotheses put forward by these authors.…”

Section: Discussioncontrasting

confidence: 99%

Estimation of plasma lipids and its significance on histopathological grades in oral cancer: Prognostic significance an original research

Sherubin

Kannan

Kumar

et al. 2013

J Oral Maxillofac Pathol

View full text Add to dashboard Cite

Background Objectives:Alterations in the lipid profile have long been associated with various cancers because lipids play a key role in maintenance of cell integrity. This study was to estimate the plasma lipid levels in patients with oral cancer and to correlate the values with the histopathological grades.Materials and Methods:The study group included 50 patients with oral cancer aged between 20 and 60 years who had visited the Department of Oral Medicine and Radiology during the period of September 2005 to July 2007. After the histotopathological confirmation, their plasma lipid levels were estimated using auto analyzer and the data was statistically analyzed.Results:The study revealed a significant decrease in the total plasma lipid levels in patients with oral cancer in comparison with the standard values. Comparing the plasma lipid levels with the histopathological grades, we observed a significant variation in the levels of total cholesterol, very low density lipoprotein, low-density lipoprotein, high-density lipoprotein and triglyceridesConclusion:The variation in the levels of plasma cholesterol and other lipid constituents in patients with cancer might be due to their increased utilization by neoplastic cells for new membrane biosynthesis. This study was an attempt to estimate the plasma lipids in oral cancer patients and its significance on histopathological grades. We observed a relationship between lower plasma lipids and oral cancer. The result of our study strongly warrants an in-depth research with larger samples and a longer follow-up to consider the low plasma lipid status in oral cancer patients as a useful indicator to assess the course and prognosis of the disease.

show abstract

Section: Discussioncontrasting

confidence: 99%

Estimation of plasma lipids and its significance on histopathological grades in oral cancer: Prognostic significance an original research

Sherubin

Kannan

Kumar

et al. 2013

J Oral Maxillofac Pathol

View full text Add to dashboard Cite

show abstract

“…FASN has been described as a possible target for chemotherapy because its expression is low or absent in most normal tissues and, in contrast, is high in a significant variety of human malignant tumors, where FASN plays important roles in proliferation [10], [12], [13], [16], [18]–[20], [22]–[25], [27], [28], [30]–[32]. As a result, FASN inhibitors are potential antitumor agents due to their ability to reduce cell proliferation and induce apoptosis [44], [47], [57], [78] without apparent toxicity to normal tissues [50], [51].…”

Section: Discussionmentioning

confidence: 99%

Fatty Acid Synthase Inhibitors Induce Apoptosis in Non-Tumorigenic Melan-A Cells Associated with Inhibition of Mitochondrial Respiration

et al. 2014

View full text Add to dashboard Cite

The metabolic enzyme fatty acid synthase (FASN) is responsible for the endogenous synthesis of palmitate, a saturated long-chain fatty acid. In contrast to most normal tissues, a variety of human cancers overexpress FASN. One such cancer is cutaneous melanoma, in which the level of FASN expression is associated with tumor invasion and poor prognosis. We previously reported that two FASN inhibitors, cerulenin and orlistat, induce apoptosis in B16-F10 mouse melanoma cells via the intrinsic apoptosis pathway. Here, we investigated the effects of these inhibitors on non-tumorigenic melan-a cells. Cerulenin and orlistat treatments were found to induce apoptosis and decrease cell proliferation, in addition to inducing the release of mitochondrial cytochrome c and activating caspases-9 and -3. Transfection with FASN siRNA did not result in apoptosis. Mass spectrometry analysis demonstrated that treatment with the FASN inhibitors did not alter either the mitochondrial free fatty acid content or composition. This result suggests that cerulenin- and orlistat-induced apoptosis events are independent of FASN inhibition. Analysis of the energy-linked functions of melan-a mitochondria demonstrated the inhibition of respiration, followed by a significant decrease in mitochondrial membrane potential (ΔΨm) and the stimulation of superoxide anion generation. The inhibition of NADH-linked substrate oxidation was approximately 40% and 61% for cerulenin and orlistat treatments, respectively, and the inhibition of succinate oxidation was approximately 46% and 52%, respectively. In contrast, no significant inhibition occurred when respiration was supported by the complex IV substrate N,N,N′,N′-tetramethyl-p-phenylenediamine (TMPD). The protection conferred by the free radical scavenger N-acetyl-cysteine indicates that the FASN inhibitors induced apoptosis through an oxidative stress-associated mechanism. In combination, the present results demonstrate that cerulenin and orlistat induce apoptosis in non-tumorigenic cells via mitochondrial dysfunction, independent of FASN inhibition.

show abstract

“…FASN is essential during embryogenesis, since Fasn−/− and Fasn+/− mice die in utero even in the presence of a diet rich in saturated fatty acids 48. Its expression is upregulated in a variety of human cancers and seems to be a prognostic marker for some of these tumors 3–15, 49. The intensity of FASN immunohistochemical positivity is stronger in human malignant melanoma than in conventional nevi or Spitz nevi,35 being associated with the Breslow thickness12, 35 and suggested as a molecular prognostic marker 12.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies provide compelling evidence that neoplastic lipogenesis is essential for cancer cell survival. In fact, several human epithelial malignancies, such as those of prostate, breast, ovary, bladder, lung, stomach and oral cavity, melanoma as well as soft tissue sarcomas overexpress FASN 3–16. For some of these tumors, such as prostate, breast and ovarian cancers and melanoma,4, 5, 9, 12 FASN overexpression has also been associated with a poor prognosis.…”

mentioning

confidence: 99%

Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model

Carvalho

Zecchin

Seguin

et al. 2008

Intl Journal of Cancer

155

129

View full text Add to dashboard Cite

Fatty acid synthase (FASN) is the enzyme responsible for the endogenous synthesis of the saturated fatty acid palmitate. In contrast to most normal cells, malignant cells depend on FASN activity for growth and survival. In fact, FASN is overexpressed in a variety of human cancers including cutaneous melanoma, in which its levels of expression are associated with a poor prognosis and depth of invasion. Here, we show that the specific inhibition of FASN activity by the antiobesity drug Orlistat or siRNA is able to significantly reduce proliferation and promote apoptosis in the mouse metastatic melanoma cell line B16-F10. These results prompted us to verify the effect of FASN inhibition on the metastatic process in a model of spontaneous melanoma metastasis, in which B16-F10 cells injected in the peritoneal cavity of C57BL/6 mice metastasize to the mediastinal lymph nodes. We observed that mice treated with Orlistat 48 hr after the inoculation of B16-F10 cells exhibited a 52% reduction in the number of mediastinal lymph node metastases, in comparison with the control animals. These results suggest that FASN activity is essential for B16-F10 melanoma cell proliferation and survival while its inactivation by Orlistat significantly reduces their metastatic spread. The chemical inhibition of FASN activity could have a potential benefit in association with the current chemotherapy for melanoma. ' 2008 Wiley-Liss, Inc.Key words: melanoma; fatty acid synthase; metastasis; Orlistat; B16-F10 cells Endogenous fatty acid synthesis from the small carbon precursors acetyl-CoA and malonyl-CoA is dependent on the activity of fatty acid synthase (FASN, EC2.3.1.85). In most of the cells, FASN is downregulated by the dietary fatty acids, with exception of lipogenic tissues as liver, lactating breast, fetal lung and adipose tissue.1,2 Recent studies provide compelling evidence that neoplastic lipogenesis is essential for cancer cell survival. In fact, several human epithelial malignancies, such as those of prostate, breast, ovary, bladder, lung, stomach and oral cavity, melanoma as well as soft tissue sarcomas overexpress FASN. [3][4][5][6][7][8][9][10][11][12][13][14][15][16] For some of these tumors, such as prostate, breast and ovarian cancers and melanoma, 4,5,9,12 FASN overexpression has also been associated with a poor prognosis. Experimental studies have shown that FASN inhibition reduces cell proliferation by blocking DNA replication during S-phase, induces apoptosis, [17][18][19][20] and decrease the size of prostate, ovarian and breast cancer xenografts. 3,21,22 In addition, the inhibition of FASN activity has a chemopreventive effect in the breast cancer transgenic neu-N mouse model. 23 Orlistat (tetrahydrolipstatin) is an irreversible inhibitor of pancreatic and gastric lipases clinically used because of its antiobesity properties that also blocks the activity of the thioesterase domain of FASN. 24 In fact, FASN inhibition by Orlistat reduces proliferation and promotes apoptosis in prostate, breast and stomach cancer cel...

show abstract

Fatty acid synthase expression is increased in neoplastic lesions of the oral tongue

Cited by 66 publications

References 10 publications

Estimation of plasma lipids and its significance on histopathological grades in oral cancer: Prognostic significance an original research

Estimation of plasma lipids and its significance on histopathological grades in oral cancer: Prognostic significance an original research

Fatty Acid Synthase Inhibitors Induce Apoptosis in Non-Tumorigenic Melan-A Cells Associated with Inhibition of Mitochondrial Respiration

Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model

Contact Info

Product

Resources

About