Increased Activity of Glycerol 3-phosphate Dehydrogenase and Other Lipogenic Enzymes in Human Bladder Cancer

Turyn, Jacek; Schlichtholz, Beata; Dettlaff-Pokora, Agnieszka; Presler, Malgorzata; Goyke, Elżbieta; Matuszewski, Marcin; Kmieć, Zbigniew; Krajka, K; Świerczyński, Julian

doi:10.1055/s-2003-43500

Cited by 78 publications

(82 citation statements)

References 23 publications

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“…ACLY overexpression or activation have been reported in urinary bladder, breast, liver, stomach, colon, and prostate tumors (21)(22)(23)(24)(25)(26). However, to the best of our knowledge, this is the first observation of ACLY activation in lung cancer.…”

Section: Discussionmentioning

confidence: 82%

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: 82%

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

show abstract

“…Distinctive elevation of ACLY expression and activity has been reported in lung, prostate, bladder, breast, liver, stomach, and colon tumors (13,(23)(24)(25)(26). In human lung adenocarcinoma, the expression of phosphorylated ACLY was correlated with stage, differentiation grade, and poor prognosis (13).…”

Section: Deregulation Of Acly In Cancer Cellsmentioning

confidence: 95%

ATP-Citrate Lyase: A Key Player in Cancer Metabolism

2012

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ATP-citrate lyase (ACLY) is a cytosolic enzyme that catalyzes the generation of acetyl CoA from citrate. Acetyl CoA is a vital building block for the endogenous biosynthesis of fatty acids and cholesterol and is involved in isoprenoid-based protein modifications. Acetyl CoA is also required for acetylation reactions that modify proteins, such as histone acetylation. ACLY is upregulated or activated in several types of cancers, and its inhibition is known to induce proliferation arrest in cancer cells both in vitro and in vivo. The present review highlights current knowledge about the role of ACLY in cancer cells, with special reference to the different pathways that are linked by ACLY. Cancer Res; 72(15);

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“…Distinctive elevation of ACLY expression and activity has been reported in lung, prostate, bladder, breast, liver, stomach, and colon tumors (18)(19)(20)(21)(22)(23)(24). Moreover, inhibition of ACLY by either RNAi or pharmacologic inhibitors results in growth arrest in tumor cells, both in vitro and in vivo (5,18,25,26).…”

Section: Introductionmentioning

confidence: 99%

ATP Citrate Lyase Knockdown Induces Growth Arrest and Apoptosis through Different Cell- and Environment-Dependent Mechanisms

Zaidi

Royaux

Swinnen

et al. 2012

Molecular Cancer Therapeutics

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ATP citrate lyase (ACLY) is a cytosolic enzyme that catalyzes generation of acetyl-CoA, which is a vital building block for fatty acid, cholesterol, and isoprenoid biosynthesis. ACLY is upregulated in several types of cancer, and its inhibition induces proliferation arrest in certain cancer cells. As ACLY is involved in several pathways, its downregulation may affect multiple processes. Here, we have shown that short hairpin RNAmediated ACLY silencing in cell lines derived from different types of cancers induces proliferation, cell-cycle arrest, and apoptosis. However, this antiproliferative effect of ACLY knockdown was observed only when cells were cultivated under lipid-reduced growth conditions. Proliferation arrest induced by ACLY silencing was partially rescued by supplementing the media with fatty acids and/or cholesterol. This indicates that the ACLY knockdown-mediated growth arrest might be the result of either fatty acid or cholesterol starvation or both. In the absence of ACLY, the cancer cells displayed elevated expression of sterol regulatory element binding protein-regulated downstream genes involved in de novo fatty acid and cholesterol biosynthesis. Furthermore, ACLY suppression resulted in elevated expression of acyl-CoA synthetase short-chain family member 2 (ACSS2), an enzyme that also produces acetyl-CoA using acetate as a substrate. Acetate supplementation partially rescued the cancer cells from ACLY suppression-induced proliferation arrest. We also observed that the absence of ACLY enhanced ACSS2-dependent lipid synthesis. These findings provide new insights into the role of ACLY in cancer cell growth and give critical information about the effects of ACLY silencing on different pathways. This information is crucial in understanding the possible application of ACLY inhibition in cancer therapeutics. Mol Cancer Ther; 11(9); 1925-35. Ó2012 AACR.

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Increased Activity of Glycerol 3-phosphate Dehydrogenase and Other Lipogenic Enzymes in Human Bladder Cancer

Cited by 78 publications

References 23 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

ATP-Citrate Lyase: A Key Player in Cancer Metabolism

ATP Citrate Lyase Knockdown Induces Growth Arrest and Apoptosis through Different Cell- and Environment-Dependent Mechanisms

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