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Quercetin: a silent retarder of fatty acid oxidation in breast cancer metastasis through steering of mitochondrial CPT1

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Abstract

Background

Recent evidence confirmed that the 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, the 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 limit the FAO in triple-negative breast cancer cells (TNBC) through an active targeting of CPT1.

Methods

Molecular quantification of QT was confirmed through high-performance thin-layer chromatography (HPTLC). Computational docking analyses predicted the binding affinity of QT to CPT1. Cell-based seahorse energy efflux investigated the mitochondrial respiration rate, glycolytic function and ATP production rate. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) investigated the FAO-associated gene expression. Matrigel cell invasion and fluorescence-activated cell sorting analyses investigated anti-metastatic and apoptotic cell death induction activities, respectively. In vivo antitumor activities were checked using the female breast cancer mice (BALB/c) model.

Results

QT resulted in a significant reduction in the intracellular mitochondrial respiration and glycolytic function, limiting extensive ATP production. In turn, QT elevated the reactive oxygen species (ROS) and depleted antioxidant levels to induce anti-metastatic and cell apoptosis activities. qRT-PCR resulted in active healing of altered FAO-associated gene expression which was well predicted through the successful in silico molecular binding potentiality of QT to CPT1. Subsequently, QT has shown excellent in vivo antitumor activities through the altered lipid profile and oxidative stress-healing capabilities.

Conclusions

All the obtained data significantly grounded the fact that QT could be a promising metabolism-targeted breast cancer therapeutic.

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Abbreviations

3D:

Three-dimensional

ACC:

Acetyl-CoA carboxylase

AMPK:

Activated protein kinase

ATP:

Adenosine triphosphate

C/EBPα:

CCAAT-enhancer-binding protein a

CPT1:

Carnitine palmitoyltransferase 1

DCF:

Dichlorofluorescein

DCFDA:

2′,7′-Dichlorofluorescein diacetate

ELISA:

Enzyme-linked immunosorbent assay

ER:

Estrogen receptor

ETC:

Electron transport chain

FAO:

Fatty acid oxidation

FASN:

Fatty acid synthase

FFA:

Free fatty acid

HBSS:

Hanks’ balanced salt solution

HER-2:

Human epidermal growth factor receptor 2

LCFA:

Long chain fatty acid

MMP:

Matrix metalloproteinase

PPARγ:

Peroxisome proliferator-activated receptor-gamma

PR:

Progesterone receptor

qRT-PCR:

Real-time quantitative reverse transcription polymerase chain reaction

QT:

Quercetin

TCA:

Tricarboxylic acid

TMB:

3,3′,5,5′-Tetramethylbenzidine

TNBC:

Triple-negative breast cancer

XP:

Extra-precision

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Acknowledgements

We thank Dr. Sib Sankar Roy (Senior scientist, CSIR-IICB, West Bengal, India) for helping us in cell-based seahorse energy efflux experimentations.

Funding

This work was not supported by any grant from funding agencies.

Author information

Authors and Affiliations

  1. Centre for Healthcare Science and Technology, Indian Institute of Engineering Science and Technology, Shibpur, Howrah, West Bengal, 711103, India

    Bhuban Ruidas, Chitrangada Das Mukhopadhyay, Koel Sinha, Sutapa Som Chaudhury & Rabindranath Majumder

  2. Department of Pharmacology, R G Kar Medical College and Hospital, Kolkata, West Bengal, 700004, India

    Tapas Kumar Sur

  3. Department of Zoology, Hooghly Mohsin College affiliated to University of Burdwan, Hooghly, West Bengal, 712101, India

    Pramita Sharma

  4. Department of Chemical Technology, University of Calcutta, 92, A. P. C. Road, Kolkata, 700009, India

    Shovonlal Bhowmick & Achintya Saha

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  1. Bhuban Ruidas
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Contributions

Conceptualization and design of study: BR. Experimentation, data acquisition and analysis: BR, TKS, KS, PS, SSC, SB, RM. Drafting manuscript: BR. Critical revision of the manuscript: CDM, AS. Study supervision: BR. All the authors have read and approved the final manuscript.

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Correspondence to Bhuban Ruidas.

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Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

All procedures performed involving animals were in accordance with the NIH guidelines and institutional animal ethical committee approval (RKC/IAEC/A/03 dated 14/12/17) for laboratory animals at R.G. Kar Medical College, Kolkata, India.

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Ruidas, B., Sur, T.K., Das Mukhopadhyay, C. et al. Quercetin: a silent retarder of fatty acid oxidation in breast cancer metastasis through steering of mitochondrial CPT1. Breast Cancer 29, 748–760 (2022). https://doi.org/10.1007/s12282-022-01356-y

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  • DOI: https://doi.org/10.1007/s12282-022-01356-y

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