Relationship between metabolic reprogramming and drug resistance in breast cancer

Lv, Lei; Yang, Song; Zhu, Yanna; Zhai, Xuguang; Li, Shuai; Tao, Xufeng; Dong, Deshi

doi:10.3389/fonc.2022.942064

Cited by 11 publications

(3 citation statements)

References 232 publications

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“…Through the phosphorylation of serine 19 by AMP kinase (AMPK) and inhibition of PDH kinase 4 (PDK 4), which inactivates PDH, E2 increases PDH activity. [ 26 ]…”

Section: Discussionmentioning

confidence: 99%

Evaluation of IP3R3 Gene Silencing Effect on Pyruvate Dehydrogenase (PDH) Enzyme Activity in Breast Cancer Cells with and Without Estrogen Receptor

Vaseghi,

Shariati,

Najafi

et al. 2024

Advanced Biomedical Research

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Background: Inositol 1,4,5-trisphosphate receptor (IP3R), a critical calcium ion (Ca2+) regulator, plays a vital role in breast cancer (BC) metabolism. Dysregulated IP3R in BC cells can drive abnormal growth or cell death. Estradiol increases IP3R type 3 (IP3R3) levels in BC, promoting cell proliferation and metabolic changes, including enhanced pyruvate dehydrogenase (PDH) activity, which, when reduced, leads to cell apoptosis. The study silenced IP3R3 to assess its impact on PDH. Materials and Methods: The study used IP3R3 small interfering RNA (siRNA) to target Michigan Cancer Foundation-7 (MCF-7) and MDA-MB-231 cell lines. Transfection success was confirmed by flow cytometry. Cell viability and gene silencing were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and real-time quantitative polymerase chain reaction (PCR) assays. Protein expression and cellular activity were analyzed through western blotting and PDH activity measurement. Results: Transfecting MCF-7 and MDA-MB-231 cells with IP3R3 siRNA achieved a 65% transfection rate without significant toxicity. IP3R3 gene silencing effectively reduced IP3R3 messenger RNA (mRNA) and protein levels in both cell lines, leading to decreased PDH enzyme activity, especially in MDA-MB-231 cells. Conclusion: The study highlights a link between high IP3R3 gene silencing and reduced PDH activity, with higher IP3R3 expression in estrogen-independent (MDA-MB-231) compared to estrogen-dependent (MCF-7) cell lines. This suggests a potential impact on BC metabolism and tumor growth via regulation of PDH activity.

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“…Through the phosphorylation of serine 19 by AMP kinase (AMPK) and inhibition of PDH kinase 4 (PDK 4), which inactivates PDH, E2 increases PDH activity. [ 26 ]…”

Section: Discussionmentioning

confidence: 99%

Evaluation of IP3R3 Gene Silencing Effect on Pyruvate Dehydrogenase (PDH) Enzyme Activity in Breast Cancer Cells with and Without Estrogen Receptor

Vaseghi,

Shariati,

Najafi

et al. 2024

Advanced Biomedical Research

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“…Different degrees of amino acid reprogramming were demonstrated in different types of BC. Specifically, the HER2 + subtype is one of the most glutamine metabolism-dependent subtypes, and the elevated levels of glutamine transporter protein (SLC1A5) and GLS transcripts in HER2 + breast cancers increased their dependence on glutamine metabolism, thus identifying new therapeutic targets for HER2 + breast cancers ( Lv et al, 2022 ). In addition, the overexpression of GLS in TNBC, which is highly resistant to Glutamine catabolism-targeted therapy was sensitive, with specific metabolic levels expressed as a low glutamine/glutamate ratio ( Wang et al, 2020 ).…”

Section: Targeting Amino Acid Metabolismmentioning

confidence: 99%

Mitochondrial inhibitors: a new horizon in breast cancer therapy

Yan,

Li,

et al. 2024

Front. Pharmacol.

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Breast cancer, due to resistance to standard therapies such as endocrine therapy, anti-HER2 therapy and chemotherapy, continues to pose a major health challenge. A growing body of research emphasizes the heterogeneity and plasticity of metabolism in breast cancer. Because differences in subtypes exhibit a bias toward metabolic pathways, targeting mitochondrial inhibitors shows great potential as stand-alone or adjuvant cancer therapies. Multiple therapeutic candidates are currently in various stages of preclinical studies and clinical openings. However, specific inhibitors have been shown to face multiple challenges (e.g., single metabolic therapies, mitochondrial structure and enzymes, etc.), and combining with standard therapies or targeting multiple metabolic pathways may be necessary. In this paper, we review the critical role of mitochondrial metabolic functions, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid cycle, and fatty acid and amino acid metabolism, in metabolic reprogramming of breast cancer cells. In addition, we outline the impact of mitochondrial dysfunction on metabolic pathways in different subtypes of breast cancer and mitochondrial inhibitors targeting different metabolic pathways, aiming to provide additional ideas for the development of mitochondrial inhibitors and to improve the efficacy of existing therapies for breast cancer.

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“…Several studies have demonstrated that metabolic reprogramming is a prominent feature in therapy resistance and aggressiveness in breast cancer cells. The metabolic milieu that characterizes T2D and often obesity provides a favorable microenvironment to support breast cancer growth, including sustained hyperglycemia and dyslipidemia ( 121 , 122 ).…”

Section: Metabolic Reprogramming In Aggressive Breast Cancer Cellsmentioning

confidence: 99%

The impact of poor metabolic health on aggressive breast cancer: adipose tissue and tumor metabolism

Sankofi,

Valencia-Rincón,

Sekhri

et al. 2023

Front. Endocrinol.

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Obesity and type 2 diabetes are chronic metabolic diseases that impact tens to hundreds of millions of adults, especially in developed countries. Each condition is associated with an elevated risk of breast cancer and with a poor prognosis after treatment. The mechanisms connecting poor metabolic health to breast cancer are numerous and include hyperinsulinemia, inflammation, excess nutrient availability, and adipose tissue dysfunction. Here, we focus on adipose tissue, highlighting important roles for both adipocytes and fibroblasts in breast cancer progression. One potentially important mediator of adipose tissue effects on breast cancer is the fibroblast growth factor receptor (FGFR) signaling network. Among the many roles of FGFR signaling, we postulate that key mechanisms driving aggressive breast cancer include epithelial-to-mesenchymal transition and cellular metabolic reprogramming. We also pose existing questions that may help better understand breast cancer biology in people with obesity, type 2 diabetes, and poor metabolic health.

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Relationship between metabolic reprogramming and drug resistance in breast cancer

Cited by 11 publications

References 232 publications

Evaluation of IP3R3 Gene Silencing Effect on Pyruvate Dehydrogenase (PDH) Enzyme Activity in Breast Cancer Cells with and Without Estrogen Receptor

Evaluation of IP3R3 Gene Silencing Effect on Pyruvate Dehydrogenase (PDH) Enzyme Activity in Breast Cancer Cells with and Without Estrogen Receptor

Mitochondrial inhibitors: a new horizon in breast cancer therapy

The impact of poor metabolic health on aggressive breast cancer: adipose tissue and tumor metabolism

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