Quercetin: Silent Retarder of Fatty Acid Oxidation in Breast Cancer Metastasis Through Steering of Mitochondrial CPT1

Abstract Recent evidence concreted that maximum energy in metastatic breast cancer progression is supplied by fatty acid oxidation (FAO) governed by a rate-limiting enzyme, carnitine palmitoyltransferase 1 (CPT1). Therefore, active limitation of FAO could be an emerging aspect to inhibit breast cancer progression. Herein, for the first time we have introduced Quercetin (QT) from a non-dietary source (Mikania micrantha Kunth) to seize the FAO in triple-negative breast cancer cells (TNBC) through an active targeting of CPT1. Apart from successive molecular quantification, QT has resulted a significant reduction in the intracellular mitochondrial respiration and glycolytic function limiting extensive ATP production. In turn, QT has elevated the reactive oxygen species (ROS) and depleted antioxidant level to induce anti-metastatic and cell apoptosis activities. Real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) investigated the FAO associated gene expression resulting significant depletion in FAO which were further confirmed through the successful in-silico molecular docking prediction for active binding potentiality of QT to CPT1. Subsequently, QT has shown an excellent in-vivo antitumor activities through the altered lipid profile and oxidative stress healing capabilities in female breast cancer BALB/c mice model. Therefore, all the obtained data significantly grounded the fact that QT could be a promising metabolism-targeted breast cancer therapeutics.

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Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation

Nature Communications ◽

10.1038/s41467-019-10592-4 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 15

Author(s):

Antoinette van Weverwijk ◽

Nikolaos Koundouros ◽

Marjan Iravani ◽

Matthew Ashenden ◽

Qiong Gao ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Metastatic Breast ◽

Acid Oxidation

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Differential MicroRNA Landscape Triggered by Estrogens in Cancer Associated Fibroblasts (CAFs) of Primary and Metastatic Breast Tumors

Cancers ◽

10.3390/cancers11030412 ◽

2019 ◽

Vol 11 (3) ◽

pp. 412 ◽

Cited By ~ 6

Author(s):

Adele Vivacqua ◽

Maria Muoio ◽

Anna Miglietta ◽

Marcello Maggiolini

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Cancer Metastasis ◽

Metastatic Breast ◽

Breast Tumors ◽

Breast Cancer Metastasis ◽

Cutaneous Metastasis ◽

Breast Cancer Progression ◽

Main Role ◽

Cancer Associated Fibroblasts

Cancer associated fibroblasts (CAFs) play a main role in breast cancer progression and metastasis. Estrogens modulate in breast CAFs the expression of microRNAs (miRNAs) that are involved in the development of many tumors. In order to provide novel insights on the regulation of miRNAs by estrogens in breast cancer, we analyzed the expression of 754 miRNAs in CAFs obtained from primary mammary tumors and CAFs derived from a cutaneous breast cancer metastasis. Using the TaqMan™ Human MicroRNA Array, we found that 17β-estradiol (E2) modulates numerous peculiar and common miRNAs in CAFs derived from primary and the metastatic malignancies. In particular, we assessed that E2 modulates 133 miRNAs (41 up and 92 downregulated) in CAFs derived from primary breast tumors, whereas E2 modulates 415 miRNAs (399 up and 16 downregulated) in CAFs derived from a cutaneous metastasis of breast carcinoma. Therefore, a number of miRNAs three times higher in metastatic CAFs with respect to primary breast CAFs was found modulated by E2. Our findings shed new light on the cumulative regulation of miRNAs by E2 in the main players of the tumor microenvironment as CAFs. Moreover, our data may be taken into consideration that is useful toward innovative prognostic and therapeutic approaches in breast cancer progression.

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Snail augments fatty acid oxidation by suppression of mitochondrial ACC2 during cancer progression

Life Science Alliance ◽

10.26508/lsa.202000683 ◽

2020 ◽

Vol 3 (7) ◽

pp. e202000683 ◽

Cited By ~ 4

Author(s):

Ji Hye Yang ◽

Nam Hee Kim ◽

Jun Seop Yun ◽

Eunae Sandra Cho ◽

Yong Hoon Cha ◽

...

Keyword(s):

Breast Cancer ◽

Fatty Acid ◽

Cancer Cells ◽

Fatty Acid Oxidation ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Acid Oxidation ◽

Mesenchymal Transition ◽

Malonyl Coa

Despite the importance of mitochondrial fatty acid oxidation (FAO) in cancer metabolism, the biological mechanisms responsible for the FAO in cancer and therapeutic intervention based on catabolic metabolism are not well defined. In this study, we observe that Snail (SNAI1), a key transcriptional repressor of epithelial–mesenchymal transition, enhances catabolic FAO, allowing pro-survival of breast cancer cells in a starved environment. Mechanistically, Snail suppresses mitochondrial ACC2 (ACACB) by binding to a series of E-boxes located in its proximal promoter, resulting in decreased malonyl-CoA level. Malonyl-CoA being a well-known endogenous inhibitor of fatty acid transporter carnitine palmitoyltransferase 1 (CPT1), the suppression of ACC2 by Snail activates CPT1-dependent FAO, generating ATP and decreasing NADPH consumption. Importantly, combinatorial pharmacologic inhibition of pentose phosphate pathway and FAO with clinically available drugs efficiently reverts Snail-mediated metabolic reprogramming and suppresses in vivo metastatic progression of breast cancer cells. Our observations provide not only a mechanistic link between epithelial–mesenchymal transition and catabolic rewiring but also a novel catabolism-based therapeutic approach for inhibition of cancer progression.

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CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1703791114 ◽

2017 ◽

Vol 114 (32) ◽

pp. E6556-E6565 ◽

Cited By ~ 40

Author(s):

Heather J. Wright ◽

Jue Hou ◽

Binzhi Xu ◽

Marvin Cortez ◽

Eric O. Potma ◽

...

Keyword(s):

Breast Cancer ◽

Fatty Acid ◽

Oxidative Phosphorylation ◽

Fatty Acid Oxidation ◽

Triple Negative Breast Cancer ◽

Cancer Metastasis ◽

Triple Negative ◽

Metastatic Potential ◽

Acid Oxidation ◽

Primary Tumors

Triple-negative breast cancer (TNBC) is notoriously aggressive with high metastatic potential, which has recently been linked to high rates of fatty acid oxidation (FAO). Here we report the mechanism of lipid metabolism dysregulation in TNBC through the prometastatic protein, CUB-domain containing protein 1 (CDCP1). We show that a “low-lipid” phenotype is characteristic of breast cancer cells compared with normal breast epithelial cells and negatively correlates with invasiveness in 3D culture. Using coherent anti-Stokes Raman scattering and two-photon excited fluorescence microscopy, we show that CDCP1 depletes lipids from cytoplasmic lipid droplets (LDs) through reduced acyl-CoA production and increased lipid utilization in the mitochondria through FAO, fueling oxidative phosphorylation. These findings are supported by CDCP1’s interaction with and inhibition of acyl CoA-synthetase ligase (ACSL) activity. Importantly, CDCP1 knockdown increases LD abundance and reduces TNBC 2D migration in vitro, which can be partially rescued by the ACSL inhibitor, Triacsin C. Furthermore, CDCP1 knockdown reduced 3D invasion, which can be rescued by ACSL3 co-knockdown. In vivo, inhibiting CDCP1 activity with an engineered blocking fragment (extracellular portion of cleaved CDCP1) lead to increased LD abundance in primary tumors, decreased metastasis, and increased ACSL activity in two animal models of TNBC. Finally, TNBC lung metastases have lower LD abundance than their corresponding primary tumors, indicating that LD abundance in primary tumor might serve as a prognostic marker for metastatic potential. Our studies have important implications for the development of TNBC therapeutics to specifically block CDCP1-driven FAO and oxidative phosphorylation, which contribute to TNBC migration and metastasis.

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A Model of Dormant-Emergent Metastatic Breast Cancer Progression Enabling Exploration of Biomarker Signatures

Molecular & Cellular Proteomics ◽

10.1074/mcp.ra117.000370 ◽

2018 ◽

Vol 17 (4) ◽

pp. 619-630 ◽

Cited By ~ 20

Author(s):

Amanda M. Clark ◽

Manu P. Kumar ◽

Sarah E. Wheeler ◽

Carissa L. Young ◽

Raman Venkataramanan ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Progression ◽

Metastatic Breast ◽

Breast Cancer Progression

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Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin

British Journal of Cancer ◽

10.1038/s41416-019-0665-5 ◽

2019 ◽

Vol 122 (2) ◽

pp. 258-265 ◽

Cited By ~ 4

Author(s):

Simon R. Lord ◽

Jennifer M. Collins ◽

Wei-Chen Cheng ◽

Syed Haider ◽

Simon Wigfield ◽

...

Keyword(s):

Breast Cancer ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Primary Breast Cancer ◽

Late Phase ◽

In Vitro Assays ◽

Acid Oxidation ◽

Clinical Trial Registration ◽

Transcriptomic Profiling

Abstract Background Epidemiological studies suggest that metformin may reduce the incidence of cancer in patients with diabetes and multiple late phase clinical trials assessing the potential of repurposing this drug are underway. Transcriptomic profiling of tumour samples is an excellent tool to understand drug bioactivity, identify candidate biomarkers and assess for mechanisms of resistance to therapy. Methods Thirty-six patients with untreated primary breast cancer were recruited to a window study and transcriptomic profiling of tumour samples carried out before and after metformin treatment. Results Multiple genes that regulate fatty acid oxidation were upregulated at the transcriptomic level and there was a differential change in expression between two previously identified cohorts of patients with distinct metabolic responses. Increase in expression of a mitochondrial fatty oxidation gene composite signature correlated with change in a proliferation gene signature. In vitro assays showed that, in contrast to previous studies in models of normal cells, metformin reduces fatty acid oxidation with a subsequent accumulation of intracellular triglyceride, independent of AMPK activation. Conclusions We propose that metformin at clinical doses targets fatty acid oxidation in cancer cells with implications for patient selection and drug combinations. Clinical Trial Registration NCT01266486.

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