Abstract 1048: Modulation of lipid metabolism through inhibition of acetyl-CoA carboxylase with ND-646 leads to potent inhibition of breast cancer cell growthin vitroandin vivo

The transcription factor hypoxia-inducible factor 1 (HIF1) is the crucial regulator of genes that are involved in metabolism under hypoxic conditions, but information regarding the transcriptional activity of HIF1 in normoxic metabolism is limited. Different tumor cells were treated under normoxic and hypoxic conditions with various drugs that affect cellular metabolism. HIF1α was silenced by siRNA in normoxic/hypoxic tumor cells, before RNA sequencing and bioinformatics analyses were performed while using the breast cancer cell line MDA-MB-231 as a model. Differentially expressed genes were further analyzed and validated by qPCR, while the activity of the metabolites was determined by enzyme assays. Under normoxic conditions, HIF1 activity was significantly increased by (i) glutamine metabolism, which was associated with the release of ammonium, and it was decreased by (ii) acetylation via acetyl CoA synthetase (ACSS2) or ATP citrate lyase (ACLY), respectively, and (iii) the presence of L-ascorbic acid, citrate, or acetyl-CoA. Interestingly, acetylsalicylic acid, ibuprofen, L-ascorbic acid, and citrate each significantly destabilized HIF1α only under normoxia. The results from the deep sequence analyses indicated that, in HIF1-siRNA silenced MDA-MB-231 cells, 231 genes under normoxia and 1384 genes under hypoxia were transcriptionally significant deregulated in a HIF1-dependent manner. Focusing on glycolysis genes, it was confirmed that HIF1 significantly regulated six normoxic and 16 hypoxic glycolysis-associated gene transcripts. However, the results from the targeted metabolome analyses revealed that HIF1 activity affected neither the consumption of glucose nor the release of ammonium or lactate; however, it significantly inhibited the release of the amino acid alanine. This study comprehensively investigated, for the first time, how normoxic HIF1 is stabilized, and it analyzed the possible function of normoxic HIF1 in the transcriptome and metabolic processes of tumor cells in a breast cancer cell model. Furthermore, these data imply that HIF1 compensates for the metabolic outcomes of glutaminolysis and, subsequently, the Warburg effect might be a direct consequence of the altered amino acid metabolism in tumor cells.

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Potent Inhibition of Breast Cancer Cell Lines by the Isoflavonoid Kievitone: Comparison with Genistein

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.1995.1855 ◽

1995 ◽

Vol 211 (2) ◽

pp. 600-606 ◽

Cited By ~ 37

Author(s):

R. Hoffman

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Cell Lines ◽

Breast Cancer Cell Lines ◽

Potent Inhibition

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Berberine Regulated Lipid Metabolism in the Presence of C75, Compound C, and TOFA in Breast Cancer Cell Line MCF-7

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2015/396035 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Wen Tan ◽

Zhangfeng Zhong ◽

Shengpeng Wang ◽

Zhanwei Suo ◽

Xian Yang ◽

...

Keyword(s):

Breast Cancer ◽

Lipid Metabolism ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Mitochondrial Function ◽

Compensatory Mechanisms ◽

Independent Manner ◽

Atp Production ◽

Compound C ◽

Mcf 7

Berberine interfering with cancer reprogramming metabolism was confirmed in our previous study. Lipid metabolism and mitochondrial function were also the core parts in reprogramming metabolism. In the presence of some energy-related inhibitors, including C75, compound C, and TOFA, the discrete roles of berberine in lipid metabolism and mitochondrial function were elucidated. An altered lipid metabolism induced by berberine was observed under the inhibition of FASN, AMPK, and ACC in breast cancer cell MCF-7. And the reversion of berberine-induced lipid suppression indicated that ACC inhibition might be involved in that process instead of FASN inhibition. A robust apoptosis induced by berberine even under the inhibition of AMPK and lipid synthesis was also indicated. Finally, mitochondrial function regulation under the inhibition of AMPK and ACC might be in an ACL-independent manner. Undoubtedly, the detailed mechanisms of berberine interfering with lipid metabolism and mitochondrial function combined with energy-related inhibitors need further investigation, including the potential compensatory mechanisms for ATP production and the upregulation of ACL.

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KDM5B promotes breast cancer cell proliferation and migration via AMPK-mediated lipid metabolism reprogramming

Experimental Cell Research ◽

10.1016/j.yexcr.2019.04.006 ◽

2019 ◽

Vol 379 (2) ◽

pp. 182-190 ◽

Cited By ~ 13

Author(s):

Zhong-Guo Zhang ◽

Hong-Sheng Zhang ◽

Hong-Liang Sun ◽

Hui-Yun Liu ◽

Min-Yao Liu ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Lipid Metabolism ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Cell Proliferation ◽

Breast Cancer Cell Proliferation ◽

Cell Proliferation And Migration ◽

And Migration ◽

Proliferation And Migration

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Exogenous Fatty Acids Modulate ER Lipid Composition and Metabolism in Breast Cancer Cells

Cells ◽

10.3390/cells10010175 ◽

2021 ◽

Vol 10 (1) ◽

pp. 175

Author(s):

Angela Maria Rizzo ◽

Irma Colombo ◽

Gigliola Montorfano ◽

Stefania Zava ◽

Paola Antonia Corsetto

Keyword(s):

Breast Cancer ◽

Fatty Acids ◽

Lipid Metabolism ◽

Cell Line ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Lipid Composition ◽

Breast Cancer Cell Lines ◽

Luminal A ◽

The Impact

(1) Background: Lipid metabolism is a fundamental hallmark of all tumors, especially of breast cancer. Few studies describe the different lipid metabolisms and sensitivities to the microenvironment of breast cancer cell subtypes that influence the proliferation, aggressiveness, and success of therapy. This study describes the impact of lipid microenvironment on endoplasmic reticulum (ER) membrane and metabolic activity in two breast cancer cell lines with Luminal A and triple-negative breast cancer (TNBC) features. (2) Methods: We investigated the peculiar lipid phenotype of a TNBC cell line, MDA-MB-231, and a Luminal A cell line, MCF7, and their different sensitivity to exogenous fatty acids (i.e., palmitic acid (PA) and docosahexaenoic acid (DHA)). Moreover, we verified the impact of exogenous fatty acids on ER lipid composition. (3) Results: The data obtained demonstrate that MDA-MB-231 cells are more sensitive to the lipid microenvironment and that both PA and DHA are able to remodel their ER membranes with consequences on resident enzyme activity. On the contrary, MCF7 cells are less sensitive to PA, whereas they incorporate DHA, although less efficiently than MDA-MB-231 cells. (4) Conclusions: This study sustains the importance of lipid metabolism as an innovative hallmark to discriminate breast cancer subclasses and to develop personalized and innovative pharmacological strategies. The different sensitivities to the lipid environment shown by MCF7 and MDA-MB-231 cells might be related to cell malignancy and chemoresistance onset. In the future, this new approach could lead to a substantial decrease both in deleterious side effects for the patients and in the cost of entire therapeutic treatments coupled with increased therapy efficiency.

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