Spot 14: A Marker of Aggressive Breast Cancer and a Potential Therapeutic Target

Kinlaw, William B.; Quinn, Jennifer L.; Wells, Wendy A.; Roser-Jones, Christopher; Moncur, Joel T.

doi:10.1210/en.2006-0463

Cited by 46 publications

(38 citation statements)

References 47 publications

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“…Systemic administration of ACC inhibitors, however, is expected to decrease levels of circulating lipids (45). Perhaps more importantly, recent findings have indicated that cancer cells express decreased levels of lipoprotein lipase (46). This would reduce the access of cancer cells to circulating lipids and provide another mechanism to render cancer tissue more prone to fatty acid depletion by ACC and FASN inhibitors than normal tissue.…”

Section: Discussionmentioning

confidence: 99%

Chemical Inhibition of Acetyl-CoA Carboxylase Induces Growth Arrest and Cytotoxicity Selectively in Cancer Cells

et al. 2007

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Development and progression of cancer is accompanied by marked changes in the expression and activity of enzymes involved in the cellular homeostasis of fatty acids. One class of enzymes that play a particularly important role in this process are the acetyl-CoA carboxylases (ACC). ACCs produce malonylCoA, an intermediate metabolite that functions as substrate for fatty acid synthesis and as negative regulator of fatty acid oxidation. Here, using the potent ACC inhibitor soraphen A, a macrocyclic polyketide from myxobacteria, we show that ACC activity in cancer cells is essential for proliferation and survival. Even at nanomolar concentrations, soraphen A can block fatty acid synthesis and stimulate fatty acid oxidation in LNCaP and PC-3M prostate cancer cells. As a result, the phospholipid content of cancer cells decreased, and cells stopped proliferating and ultimately died. LNCaP cells predominantly died through apoptosis, whereas PC-3M cells showed signs of autophagy. Supplementation of the culture medium with exogenous palmitic acid completely abolished the effects of soraphen A and rescued the cells from cell death. Interestingly, when added to cultures of premalignant BPH-1 cells, soraphen A only slightly affected cell proliferation and did not induce cell death. Together, these findings indicate that cancer cells have become dependent on ACC activity to provide the cell with a sufficient supply of fatty acids to permit proliferation and survival, introducing the concept of using small-molecule ACC inhibitors as therapeutic agents for cancer. [Cancer Res 2007;67(17):8180-7]

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Section: Discussionmentioning

confidence: 99%

Chemical Inhibition of Acetyl-CoA Carboxylase Induces Growth Arrest and Cytotoxicity Selectively in Cancer Cells

et al. 2007

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“…Increased lipid production has been linked to an increased need for membranes during rapid cell proliferation, and is considered to be part of a more general metabolic transformation that provides cancer cells with more autonomy in terms of their supply of building blocks for growth (5). In support of this hypothesis, blockade of lipogenesis by chemical inhibitors or RNA interference (RNAi)-mediated silencing of lipogenic enzymes or their regulators attenuates cell proliferation and ultimately leads to cell death (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). In several cancer types, overexpression of lipogenic enzymes is observed very early in cancer development and is independent of the proliferative status of the individual cells (17,18).…”

Section: Introductionmentioning

confidence: 99%

De novo Lipogenesis Protects Cancer Cells from Free Radicals and Chemotherapeutics by Promoting Membrane Lipid Saturation

et al. 2010

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Activation of de novo lipogenesis in cancer cells is increasingly recognized as a hallmark of aggressive cancers and has been implicated in the production of membranes for rapid cell proliferation. In the current report, we provide evidence that this activation has a more profound role. Using a mass spectrometry-based phospholipid analysis approach, we show that clinical tumor tissues that display the lipogenic phenotype show an increase in the degree of lipid saturation compared with nonlipogenic tumors. Reversal of the lipogenic switch in cancer cells by treatment with the lipogenesis inhibitor soraphen A or by targeting lipogenic enzymes with small interfering RNA leads to a marked decrease in saturated and mono-unsaturated phospholipid species and increases the relative degree of polyunsaturation. Because polyunsaturated acyl chains are more susceptible to peroxidation, inhibition of lipogenesis increases the levels of peroxidation end products and renders cells more susceptible to oxidative stress-induced cell death. As saturated lipids pack more densely, modulation of lipogenesis also alters lateral and transversal membrane dynamics as revealed by diffusion of membrane-targeted green fluorescent protein and by the uptake and response to doxorubicin. These data show that shifting lipid acquisition from lipid uptake toward de novo lipogenesis dramatically changes membrane properties and protects cells from both endogenous and exogenous insults. These findings provide important new insights into the role of de novo lipogenesis in cancer cells, and they provide a rationale for the use of lipogenesis inhibitors as antineoplastic agents and as chemotherapeutic sensitizers. Cancer Res; 70(20); 8117-26. ©2010 AACR.

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“…In contrast to most normal cells, many cancer cells display a high rate of de novo fatty acid synthesis (21). Overexpression of FASN and Spot 14 has been linked to the lipogenic malignant phenotype that has been identified in a variety of common human cancers (8). This raises the possibility of therapy that takes advantage of the aberrant lipid metabolism of malignant cells.…”

Section: Discussionmentioning

confidence: 99%

“…Spot 14, a nuclear protein associated with transcriptional activation of several enzymes of the fatty acid synthetic pathway, is also highly expressed in lipogenic tumors (6,7). High levels of FASN and Spot 14 confer a survival advantage to tumor cells, and predict a poor prognosis in breast cancer (5,6,8). Accordingly, there has been significant investigative interest in manipulating this metabolic pathway for therapeutic effect.…”

Section: Introductionmentioning

confidence: 99%

Fatty acid synthesis is a therapeutic target in human liposarcoma

Olsen

Eisenberg²,

Kuemmerle³

et al. 2010

Int J Oncol

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Abstract. Liposarcomas (LS) are mesenchymal tumors that can recur after surgical resection and often do not respond to presently available medical therapies. This study demonstrates the dependence of LS on de novo long-chain fatty acid synthesis for growth. Lipogenesis can be impaired by inhibiting the activities of lipogenic enzymes, including acetyl CoA-carboxylase (ACC) and fatty acid synthase (FASN), or by suppressing the expression of key genes involved in the pathway and its regulation. The FASN inhibitors cerulenin and orlistat reduced the growth of two LS cell lines (LiSa2, SW872), as did inhibition of ACC with soraphen A. CDDOMe, a synthetic triterpenoid, suppressed expression of Spot 14 and FASN genes and likewise inhibited LS cell growth. Importantly, the anti-proliferative effect of each agent was prevented by the co-administration of palmitate, the major product of cellular long-chain fatty acid synthesis. In stark contrast to LS cells, these compounds had no effect on the growth of fibroblasts. Four biochemically distinct agents that target critical points in the fatty acid synthetic pathway exert anti-proliferative effects on LS cells, and rescue of cell growth by palmitic acid suggests that reduced tumor cell lipogenesis mediates the growth inhibition. These findings warrant further studies aimed at the clinical exploitation of the dependence of LS cell growth on fatty acids.

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Spot 14: A Marker of Aggressive Breast Cancer and a Potential Therapeutic Target

Cited by 46 publications

References 47 publications

Chemical Inhibition of Acetyl-CoA Carboxylase Induces Growth Arrest and Cytotoxicity Selectively in Cancer Cells

Chemical Inhibition of Acetyl-CoA Carboxylase Induces Growth Arrest and Cytotoxicity Selectively in Cancer Cells

De novo Lipogenesis Protects Cancer Cells from Free Radicals and Chemotherapeutics by Promoting Membrane Lipid Saturation

Fatty acid synthesis is a therapeutic target in human liposarcoma

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