Fatty Acid Synthase Inhibition by Amentoflavone Suppresses HER2/<i>neu</i> (erbB2) Oncogene in SKBR3 Human Breast Cancer Cells

Lee, Jin Sung; Sul, Ji Young; Park, Jun‐Beom; Lee, Myung Sun; Young, Eun; Song, In Sang; Kim, Je Ryong; Chang, Euijin

doi:10.1002/ptr.4778

Cited by 69 publications

(46 citation statements)

References 30 publications

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“…FASN expression has been reported to be regulated by the human epidermal growth factor receptor HER2 oncogene (erbB2) through phosphatidylinositol 3-kinase (PI3-K)/Akt in breast cancers [63] as well as by mTOR signaling pathways in colorectal cancer cells [64]. Inhibition of HER2 expression can suppress Akt, mTOR, and JNK activity that leads to suppression of FASN expression and induction of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

The Selective Target of Capsaicin on FASN Expression and De Novo Fatty Acid Synthesis Mediated through ROS Generation Triggers Apoptosis in HepG2 Cells

et al. 2014

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The inhibition of the mammalian de novo synthesis of long-chain saturated fatty acids (LCFAs) by blocking the fatty acid synthase (FASN) enzyme activity in tumor cells that overexpress FASN can promote apoptosis, without apparent cytotoxic to non-tumor cells. The present study aimed to focus on the potent inhibitory effect of capsaicin on the fatty acid synthesis pathway inducing apoptosis of capsaicin in HepG2 cells. The use of capsaicin as a source for a new FASN inhibitor will provide new insight into its possible application as a selective anti-cancer therapy. The present findings showed that capsaicin promoted apoptosis as well as cell cycle arrest in the G0/G1 phase. The onset of apoptosis was correlated with a dissipation of mitochondrial membrane potential (ΔΨm). Apoptotic induction by capsaicin was mediated by inhibition of FASN protein expression which was accompanied by decreasing its activity on the de novo fatty acid synthesis. The expression of FASN was higher in HepG2 cells than in normal hepatocytes that were resistant to undergoing apoptosis following capsaicin administration. Moreover, the inhibitory effect of capsaicin on FASN expression and activity was found to be mediated by an increase of intracellular reactive oxygen species (ROS) generation. Treatment of HepG2 cells with capsaicin failed to alter ACC and ACLY protein expression, suggesting ACC and ACLY might not be the specific targets of capsaicin to induce apoptosis. An accumulation of malonyl-CoA level following FASN inhibition represented a major cause of mitochondrial-dependent apoptotic induction instead of deprivation of fatty acid per se. Here, we also obtained similar results with C75 that exhibited apoptosis induction by reducing the levels of fatty acid without any change in the abundance of FASN expression along with increasing ROS production. Collectively, our results provide novel evidence that capsaicin exhibits a potent anti-cancer property by targeting FASN protein in HepG2 cells.

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Section: Discussionmentioning

confidence: 99%

The Selective Target of Capsaicin on FASN Expression and De Novo Fatty Acid Synthesis Mediated through ROS Generation Triggers Apoptosis in HepG2 Cells

et al. 2014

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“…In previous reports, the addition of exogenous palmitate mark edly suppresses the cytotoxic effects of natural FASN inhibi tors such as luteolin and amentoflavone in breast cancer cell lines. 38,39) 25) The JNK pathway rep resents one subgroup of MAPK and plays a role in the induc tion of apoptosis, cell survival, and proliferation. 42) JNK sig naling plays a role in FASN expression and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Anticancer Activity of Pristimerin in Epidermal Growth Factor Receptor 2-Positive SKBR3 Human Breast Cancer Cells

Lee

Yoon

Lee

et al. 2013

Biological & Pharmaceutical Bulletin

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Pristimerin is a naturally occurring triterpenoid that causes cytotoxicity in several cancer cell lines. However, the mechanism of action for the cytotoxic effect of pristimerin has not been unexplored. The purpose of this study was to investigate the effect of pristimerin on cytotoxicity using the epidermal growth factor receptor 2 (HER2)-positive SKBR3 human breast cancer cell line. Pristimerin inhibited proliferation in dose-and time-dependent manners in cells. We found it to be effective for suppressing HER2 protein and mRNA expression. Fatty acid synthase (FASN) expression and FASN activity were downregulated by pristimerin. Adding of exogenous palmitate, the end product of de novo fatty acid synthesis, reduced the proliferation activity of pristimerin. The changes in HER2 and FASN expression induced by pristimerin altered the levels of Akt and mitogen-activated protein kinase (MAPK) phosphorylation (Erk1/2, p38, and c-Jun N-terminal kinase (JNK)). Pristimerin lowered the levels of phosphorylated mammalian target of rapamycin (mTOR) and its downstream targets such as phosphoprotein 70 ribosomal protein S6 kinase and 4E binding protein1. Pristimerin inhibited migration and invasion of cells, and co-treatment with the mTOR inhibitor rapamycin additionally suppressed these activities. Pristimerin-induced apoptosis was evaluated using Western blotting for caspase-3, -8, -9, and poly (ADP-ribose) polymerase expression and flow cytometric analysis for propidium iodide labeling. These results suggest that pristimerin is a novel HER2-downregulated compound that is able to decrease fatty acid synthase and modulate the Akt, MAPK, and mTOR signaling pathways to influence metastasis and apoptosis. Pristimerin may be further evaluated as a chemotherapeutic agent for HER2-positive breast cancers.

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“…In different HER+ breast and ovarian cancer cell-lines, i.e. in SK-BR-3, BT474, MDA-MB-453, T47D (moderate HER2 expression), MCF-7 (low expression), and SK-OV-3, downregulation of HER2 has been recorded by inhibition of fatty acid synthase (FASN), which catalyzes the formation of longchain fatty acids [132], [133]. It appears that there is an intimate connection between FASN and HER2, both of which positively regulate each other.…”

Section: Breast Cancer and Her2 In Obesity: In Vitro And In Vivo Obsementioning

confidence: 99%

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

Ray

2017

Hormone Molecular Biology and Clinical Investigation

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Abstract:Obesity is associated with the risk of several health disorders including certain cancers. Among obesity-related cancers, postmenopausal breast carcinoma is a well-studied one. Apart from an increase in certain types of lipids in obesity, excess adipose tissue releases many hormone-like cytokines/adipokines, which are usually pro-inflammatory in nature. Leptin is one of such adipokines and significantly linked with the intracellular signaling pathways of other growth factors such as insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2). In general, HER2 is overexpressed in roughly 30% of breast carcinomas; its presence indicates aggressive tumor behavior. Conversely, HER2 has certain effects in normal conditions such as differentiation of preadipocytes, cardiovascular health and vitamin D metabolism. HER2 has no known endogenous ligand, but it may form dimers with other three members of the epidermal growth factor receptor (EGFR) family and can activate downstream signaling pathways. Furthermore, HER2 is intimately connected with several enzymes, e.g. fatty acid synthase (FASN), phosphatidylinositol 3-kinase (PI3K), AKT and mechanistic target of rapamycin (mTOR), all of which play significant regulatory roles in lipogenic pathways or lipid metabolism. In obesity-related carcinogenesis, characteristics like insulin resistance and elevated IGF-1 are commonly observed. Both IGF-1 and leptin can modulate EGFR and HER2 signaling pathways. Although clinical studies have shown mixed results, the behavior of HER2+ tumor cells including HER2 levels can be altered by several factors such as obesity, leptin and fatty acids. A precise knowledge is useful in new therapeutic approaches against HER+ tumors.

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Fatty Acid Synthase Inhibition by Amentoflavone Suppresses HER2/neu (erbB2) Oncogene in SKBR3 Human Breast Cancer Cells

Cited by 69 publications

References 30 publications

The Selective Target of Capsaicin on FASN Expression and De Novo Fatty Acid Synthesis Mediated through ROS Generation Triggers Apoptosis in HepG2 Cells

The Selective Target of Capsaicin on FASN Expression and De Novo Fatty Acid Synthesis Mediated through ROS Generation Triggers Apoptosis in HepG2 Cells

Anticancer Activity of Pristimerin in Epidermal Growth Factor Receptor 2-Positive SKBR3 Human Breast Cancer Cells

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

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