Fatty acid synthase gene overexpression and copy number gain in prostate adenocarcinoma☆

Shah, Uzma; Dhir, Rajiv; Gollin, Susanne M.; Chandran, Uma; Lewis, Dale; Acquafondata, Marie; Pflug, Beth R.

doi:10.1016/j.humpath.2005.11.022

Cited by 108 publications

(77 citation statements)

References 24 publications

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“…FASN, which is a downstream de novo lipogenic enzyme of ACLY, is frequently overexpressed in many cancers. Interestingly, the genes of key lipogenic enzymes including acetyl-CoA carboxylase (ACC), FASN, and ACLY are all located at the 17q chromosome, and gene amplification has been reported in prostate cancer (36). Importantly, inhibition of FASN induces apoptosis in a variety of cancer cells concomitant with the decrease in phospholipids (37,38).…”

Section: Discussionmentioning

confidence: 99%

ATP Citrate Lyase: Activation and Therapeutic Implications in Non–Small Cell Lung Cancer

Migita¹,

Narita

Nomura³

et al. 2008

Cancer Research

340

282

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Enhanced glucose and lipid metabolism is one of the most common properties of malignant cells. ATP citrate lyase (ACLY) is a key enzyme of de novo fatty acid synthesis responsible for generating cytosolic acetyl-CoA and oxaloacetate. To evaluate its role in lung cancer progression, we here analyzed ACLY expression in a subset of human lung adenocarcinoma cell lines and showed a relationship with the phosphatidyl-inositol-3 kinase-Akt pathway. The introduction of constitutively active Akt into cells enhanced the phosphorylation of ACLY, whereas dominant-negative Akt caused attenuation. In human lung adenocarcinoma samples, ACLY activity was found to be significantly higher than in normal lung tissue. Immunohistochemical analysis further showed phosphorylated ACLY overexpression in 162 tumors, well-correlating with stage, differentiation grade, and a poorer prognosis. Finally, to show the therapeutic potential and mechanism of ACLY inhibition for lung cancer treatment, we assessed the effect of RNA interference targeting ACLY on lipogenesis and cell proliferation in A549 cells. ACLY inhibition resulted in growth arrest in vitro and in vivo. Interestingly, increased intracellular lipids were found in ACLY knockdown cells, whereas de novo lipogenesis was inhibited. Supplementation of insulin could rescue the proliferative arrest elicited by ACLY inhibition; however, in contrast, fatty acid palmitate induced cell death. Taken together, these findings suggest that ACLY is involved in lung cancer pathogenesis associated with metabolic abnormality and might offer a novel therapeutic target. [Cancer Res 2008;68(20):8547-54]

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Section: Discussionmentioning

confidence: 99%

ATP Citrate Lyase: Activation and Therapeutic Implications in Non–Small Cell Lung Cancer

Migita¹,

Narita

Nomura³

et al. 2008

Cancer Research

340

282

View full text Add to dashboard Cite

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“…In breast cancer BT-474 cells that overexpress HER2, the expression of FASN and ACC are not mediated by SREBP-1, but by a mammalian target of rapamycin (mTOR)-dependent selective translational induction (Yoon et al, 2007). A significant copy number gain of FASN gene is also observed in prostate adenocarcinoma (Shah et al, 2006). These observations suggest that tumour-related FASN overexpression could be regulated at multiple levels (Figure 1).…”

Section: Regulation Of Fasn and De Novo Fatty-acid Synthesis Pathway mentioning

confidence: 99%

De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy

2009

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“…Immunohistochemical studies have reported high levels of FASN in cancers of the ovary, breast, lung, prostate and endometrium. [5][6][7][8][9] Recently Alo et al, examined FASN expression in PDA and showed that higher expression levels correlated with advanced tumor stage and poor survival. 10 Caveolin-1 (Cav-1) is the principal protein component of caveolae, which are located at the cell surface in most cell types.…”

Section: Introductionmentioning

confidence: 99%

Co-expression of fatty acid synthase and caveolin-1 in pancreatic ductal adenocarcinoma: Implications for tumor progression and clinical outcome

Witkiewicz¹,

Nguyen²,

Dasgupta³

et al. 2008

Cell Cycle

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Pancreatic cancer is a devastating disease that afflicts over 35,000 Americans every year. Since therapeutic options are limited, understanding the molecular aspects of this disease is critical for moving towards targeted treatment of this aggressive form of cancer. Caveolin-1 (Cav-1) and fatty acid synthase (FASN) are two proteins that have been shown to be dysregulated in a number of cancers. Functionally these proteins have been shown to be involved in the process of tumorigenesis. We thus surveyed the expression of both these critical proteins in a series of pancreatic precancerous lesions (pancreatic intraepithelial neoplasia, PanIN) and pancreatic cancers. Cav-1 and FASN expression correlated predominantly with clinical characteristics, such as histologic grade and advanced tumor stage (e.g., high Cav-1 and FASN expression correlated with poor differentiation status) and a significant survival advantage was found in patients with low co-expressing FASN and Cav-1 tumors. Cav-1 and FASN expression was absent in PanIN lesions and the normal ducts and acini. Of note, Cav-1 expression was detected in the fibroblasts of the desmoplastic pancreatic cancer stroma, but not in stromal cells of the normal pancreas. Mechanistically, these data support the notion that these proteins are co-regulated either directly or indirectly by another factor. Importantly, the co-expression of these proteins significantly correlates with clinical features and survival status of pancreatic cancer patients. Thus, Cav-1 and FASN may functionally cooperate in the process of pancreatic tumorigenesis, and as such, may be good candidate prognostic markers and targets for therapeutic intervention.

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Fatty acid synthase gene overexpression and copy number gain in prostate adenocarcinoma☆

Cited by 108 publications

References 24 publications

ATP Citrate Lyase: Activation and Therapeutic Implications in Non–Small Cell Lung Cancer

ATP Citrate Lyase: Activation and Therapeutic Implications in Non–Small Cell Lung Cancer

De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy

Co-expression of fatty acid synthase and caveolin-1 in pancreatic ductal adenocarcinoma: Implications for tumor progression and clinical outcome

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