Cytosolic acetyl‐CoA synthetase affected tumor cell survival under hypoxia: the possible function in tumor acetyl‐CoA/acetate metabolism

Yoshii, Yukie; Furukawa, Takako; Yoshii, Hiroshi; Mori, Tetsuya; Kiyono, Yasushi; Waki, Atsuo; Kobayashi, Masato; Tsujikawa, Tetsuya; Kudo, Takashi; Okazawa, Hidehiko; Yonekura, Yoshiharu; Fujibayashi, Yasuhisa

doi:10.1111/j.1349-7006.2009.01099.x

Cited by 102 publications

(96 citation statements)

References 39 publications

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“…Fatty acid synthesis precursors can be produced via other metabolic pathways, such as glutamine (55,56). For example, in tumor cells with defective mitochondria, reductive carboxylation of glutamine-derived ␣-ketoglutarate produces citrate to support de novo lipogenesis (55).…”

Section: Discussionmentioning

confidence: 99%

Glucose-dependent de Novo Lipogenesis in B Lymphocytes

Dufort

Gumina

et al. 2014

Journal of Biological Chemistry

145

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Background:The metabolic requirements underlying B lymphocyte differentiation are poorly understood. Results: Differentiation is accompanied by glucose metabolism into fatty acid and cholesterol synthesis, mediated by ATPcitrate lyase (ACLY). Conclusion: ACLY-dependent lipogenesis is required for several phenotypic changes defining plasma cell differentiation. Significance: This study proposes a critical role for ACLY coupled glucose-dependent de novo lipogenesis in LPS-induced B lymphocyte differentiation.

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Section: Discussionmentioning

confidence: 99%

Glucose-dependent de Novo Lipogenesis in B Lymphocytes

Dufort

Gumina

et al. 2014

Journal of Biological Chemistry

145

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“…The cytosolic enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2) also produces acetyl-CoA using acetate as a substrate (ref. 27; Fig. 1).…”

Section: Introductionmentioning

confidence: 94%

“…7B). It shows that coinhibition of the 2 pathways known to be involved in cytosolic acetyl-CoA production in cancer cells (5,27,38,39) is highly cytotoxic for the cells.…”

Section: In Acly-deficient Cancer Cells Acss2 May Compensate For Thementioning

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

101

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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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“…One ACS in mammalian cells (AceCS1) also has functions that compensate for ACL (70) but does not have any significant phenotype when silenced (25,46). The other ACS (AceCS2), however, has been shown to be functional under hypoxic conditions (71). Mammalian ACL, therefore, seems to have more important roles in cell proliferation and lipid biosynthesis than the ACSs (5,70).…”

Section: Discussionmentioning

confidence: 99%

Functional Analyses of Two Acetyl Coenzyme A Synthetases in the Ascomycete Gibberella zeae

et al. 2011

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Acetyl coenzyme A (acetyl-CoA) is a crucial metabolite for energy metabolism and biosynthetic pathways and is produced in various cellular compartments with spatial and temporal precision. Our previous study on ATP citrate lyase (ACL) in Gibberella zeae revealed that ACL-dependent acetyl-CoA production is important for histone acetylation, especially in sexual development, but is not involved in lipid synthesis. In this study, we deleted additional acetyl-CoA synthetic genes, the acetyl-CoA synthetases (ACS genes ACS1 and ACS2), to identify alternative acetyl-CoA production mechanisms for ACL. The ACS1 deletion resulted in a defect in sexual development that was mainly due to a reduction in 1-palmitoyl-2-oleoyl-3-linoleoyl-rac-glycerol production, which is required for perithecium development and maturation. Another ACS coding gene, ACS2, has accessorial functions for ACS1 and has compensatory functions for ACL as a nuclear acetyl-CoA producer. This study showed that acetate is readily generated during the entire life cycle of G. zeae and has a pivotal role in fungal metabolism. Because ACSs are components of the pyruvate-acetaldehyde-acetate pathway, this fermentation process might have crucial roles in various physiological processes for filamentous fungi.

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Cytosolic acetyl‐CoA synthetase affected tumor cell survival under hypoxia: the possible function in tumor acetyl‐CoA/acetate metabolism

Cited by 102 publications

References 39 publications

Glucose-dependent de Novo Lipogenesis in B Lymphocytes

Glucose-dependent de Novo Lipogenesis in B Lymphocytes

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

Functional Analyses of Two Acetyl Coenzyme A Synthetases in the Ascomycete Gibberella zeae

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