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

Mashima, Tetsuo; Seimiya, Hiroyuki; Tsuruo, Takashi

doi:10.1038/sj.bjc.6605007

Cited by 454 publications

(372 citation statements)

References 33 publications

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“…Since phospholipid biosynthesis, but not glycerol phosphate shuttling, occurs in the endoplasmic reticulum, we can assume that SLC37A1 protein could have a role in the transport of G3P into endoplasmic reticulum to provide phospholipid biosynthesis. Fatty acid synthase (FAS), the main enzyme involved in de novo fatty acid synthesis, is coordinately regulated at the transcriptional level together with other lipogenic genes to provide balanced amounts of lipids for membrane biosynthesis [7,13]. FAS concentration is very low in non-cancerous cells, while it is overexpressed in a wide variety of human cancer cells, supporting the synthesis of phospholipids required for the newly synthesized cellular membrane [31].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to FAS, several other enzymes involved in lipid metabolism have recently been shown to be implicated in tumor growth and viability [13]. In mammals, two ACS isozymes, ACSL4 and ACSL5, GPAT enzymes, and the LPAAT-b isoform are all overexpressed by a number of human cancers cells, including glioma, lung, breast, and colon carcinoma [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

“…Among the enzymes involved in lipid biosynthesis in tumor cells, the most studied is FAS, which is regulated by different growth factor signaling, including epidermal growth factor (EGF), as well as by steroid hormoneinduced transduction pathways, including estradiol (E2) and its cognate receptor (ER) [13,18]. Downstream of the growth factors and steroid receptors, the phosphatidylinositol-3-kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) signaling pathways have been suggested to mediate FAS expression through the sterol regulatory element-binding protein 1c (SREBP-1c) [13,18].…”

Section: Introductionmentioning

confidence: 99%

“…Downstream of the growth factors and steroid receptors, the phosphatidylinositol-3-kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) signaling pathways have been suggested to mediate FAS expression through the sterol regulatory element-binding protein 1c (SREBP-1c) [13,18]. However, the up-regulation of FAS by activated growth factor receptors requires a complex signaling network [19,20].…”

Section: Introductionmentioning

confidence: 99%

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SLC37A1 Gene expression is up-regulated by epidermal growth factor in breast cancer cells

Iacopetta

Lappano

Cappello

et al. 2009

Breast Cancer Res Treat

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Phospholipid biosynthesis exerts an important role in the proliferation of tumor cells; however, the regulation of the proteins involved in this context still remains to be fully evaluated. SLC37A1 protein belongs to a small family of sugar-phosphate/phosphate exchangers. The sequence homology with the bacterial glycerol-3-phosphate transporter (30%) suggests that SLC37A1 might be able to catalyze an exchange of glycerol-3-phosphate against phosphate. Glycerol-3-phosphate, found in different cellular compartments, is a fundamental substrate in phospholipid biosynthesis. In the present study, we demonstrate for the first time that epidermal growth factor (EGF) transactivates SLC37A1 promoter sequence and induces SLC37A1 mRNA, and protein expression through the EGFR/MAPK/ Fos transduction pathway in ER-negative SkBr3 breast cancer cells. These findings were corroborated by comparable results obtained in ER-positive endometrial Ishikawa tumor cells. Interestingly, we also show that SLC37A1 protein localizes in the endoplasmic reticulum, hence supporting its possible involvement in phospholipid biosynthesis. On the basis of our data, the up-regulation of SLC37A1 gene expression should be included among the well-known stimulatory action exerted by EGF in breast cancer cells. In addition, further studies are required to provide evidence concerning the potential role of EGFmediated SLC37A1 induction in breast tumor cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

SLC37A1 Gene expression is up-regulated by epidermal growth factor in breast cancer cells

Iacopetta

Lappano

Cappello

et al. 2009

Breast Cancer Res Treat

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“…In this study, we focused on the investigation of positive feedback loop. FASN is a complex multifunctional enzyme that plays a central role in endogenous lipogenesis in mammals [28,29] . It has been reported that the overexpression of FASN together with a high proliferative index of breast cancer cells are associated with a nine-fold increased risk of patient mortality [30] .…”

Section: Discussionmentioning

confidence: 99%

A novel positive feedback loop involving FASN/p-ERK1/2/5-LOX/LTB4/FASN sustains high growth of breast cancer cells

Zhao

et al. 2011

Acta Pharmacol Sin

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Aim:To investigate the endogenous signaling pathways associated with high proliferation potential of breast cancer cells. Methods: Breast cancer cell lines LM-MCF-7 and MCF-7 with high and low proliferation capability were used. The promoter activity of fatty acid synthase (FASN) was examined using luciferase reporter gene assay. The expression level of FASN mRNA was measured using RT-PCR and real time PCR, respectively. The level of leukotriene B4 (LTB4) was determined with ELISA. The expression levels of 5-lipoxygenase (5-LOX) was analyzed using RT-PCR and Western blot, respectively. 5-Bromo-20-deoxyuridine (BrdU) incorporation assay was used to study the proliferation of LM-MCF-7 and MCF-7 cells.

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Autophagy activation and SREBP‐1 induction contribute to fatty acid metabolic reprogramming by leptin in breast cancer cells

2020

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Leptin, a hormone predominantly derived from adipose tissue, is well known to induce growth of breast cancer cells. However, its underlying mechanisms remain unclear. In this study, we examined the role of reprogramming of lipid metabolism and autophagy in leptin-induced growth of breast cancer cells. Herein, leptin induced significant increase in fatty-acid-oxidation (FAO)dependent ATP production in estrogen receptor-positive breast cancer cells. Furthermore, leptin induced both free fatty acid (FFA) release and intracellular lipid accumulation, indicating a multifaceted effect of leptin in fatty acid metabolism. These findings were further validated in an MCF-7 tumor xenograft mouse model. Importantly, all the aforementioned metabolic effects of leptin were mediated via autophagy activation. In addition, SREBP-1 induction driven by autophagy and fatty acid synthase induction, which is mediated by SREBP-1, play crucial roles in leptinstimulated metabolic reprogramming and are required for growth of breast cancer cell, suggesting a pivotal contribution of fatty acid metabolic reprogramming to tumor growth by leptin. Taken together, these results highlighted a crucial role of autophagy in leptin-induced cancer cell-specific metabolism, which is mediated, at least in part, via SREBP-1 induction.

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

Cited by 454 publications

References 33 publications

SLC37A1 Gene expression is up-regulated by epidermal growth factor in breast cancer cells

SLC37A1 Gene expression is up-regulated by epidermal growth factor in breast cancer cells

A novel positive feedback loop involving FASN/p-ERK1/2/5-LOX/LTB4/FASN sustains high growth of breast cancer cells

Autophagy activation and SREBP‐1 induction contribute to fatty acid metabolic reprogramming by leptin in breast cancer cells

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