Preventing feedback activation of glycolytic ATP production enhances metformin cytotoxicity in breast cancer cells when oxidative phosphorylation is inhibited

Metabolic rewiring to utilize aerobic glycolysis is a hallmark of cancer. However, recent findings suggest the role of mitochondria in energy generation in cancer cells and the metabolic switch to oxidative phosphorylation (OXPHOS) in response to the blockade of glycolysis. We previously demonstrated that the antitumor effect of gracillin occurs through the inhibition of mitochondrial complex II-mediated energy production. Here, we investigated the potential of gracillin as an anticancer agent targeting both glycolysis and OXPHOS in breast and lung cancer cells. Along with the reduction in adenosine triphosphate (ATP) production, gracillin markedly suppresses the production of several glycolysis-associated metabolites. A docking analysis and enzyme assay suggested phosphoglycerate kinase 1 (PGK1) is a potential target for the antiglycolytic effect of gracillin. Gracillin reduced the viability and colony formation ability of breast cancer cells by inducing apoptosis. Gracillin displayed efficacious antitumor effects in mice bearing breast cancer cell line or breast cancer patient-derived tumor xenografts with no overt changes in body weight. An analysis of publicly available datasets further suggested that PGK1 expression is associated with metastasis status and poor prognosis in patients with breast cancer. These results suggest that gracillin is a natural anticancer agent that inhibits both glycolysis and mitochondria-mediated bioenergetics.

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CCL5 activation of CCR5 regulates cell metabolism to enhance proliferation of breast cancer cells

Open Biology ◽

10.1098/rsob.160122 ◽

2016 ◽

Vol 6 (6) ◽

pp. 160122 ◽

Cited By ~ 25

Author(s):

Darrin Gao ◽

Ramtin Rahbar ◽

Eleanor N. Fish

Keyword(s):

Breast Cancer ◽

Glucose Uptake ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Tumour Cells ◽

Mammary Tumour ◽

Dependent Manner ◽

Atp Production ◽

Primary Mouse ◽

Mcf 7

In earlier studies, we showed that CCL5 enhances proliferation and survival of MCF-7 breast cancer cells in an mTOR-dependent manner and we provided evidence that, for T cells, CCL5 activation of CCR5 results in increased glycolysis and enhanced ATP production. Increases in metabolic activity of cancer cells, specifically increased glycolytic activity and increased expression of glucose transporters, are associated with tumour progression. In this report, we provide evidence that CCL5 enhances the proliferation of human breast cancer cell lines (MDA-MB-231, MCF-7) and mouse mammary tumour cells (MMTV-PyMT), mediated by CCR5 activation. Concomitant with enhanced proliferation we show that CCL5 increases cell surface expression of the glucose transporter GLUT1, and increases glucose uptake and ATP production by these cells. Blocking CCL5-inducible glucose uptake abrogates the enhanced proliferation induced by CCL5. We provide evidence that increased glucose uptake is associated with enhanced glycolysis, as measured by extracellular acidification. Moreover, CCL5 enhances the invasive capacity of these breast cancer cells. Using metabolomics, we demonstrate that the metabolic signature of CCL5-treated primary mouse mammary tumour cells reflects increased anabolic metabolism. The implications are that CCL5–CCR5 interactions in the tumour microenvironment regulate metabolic events, specifically glycolysis, to promote tumour proliferation and invasion.

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Total Cellular ATP Production Changes With Primary Substrate in MCF7 Breast Cancer Cells

Frontiers in Oncology ◽

10.3389/fonc.2020.01703 ◽

2020 ◽

Vol 10 ◽

Author(s):

Maggie C. Louie ◽

Justin Ton ◽

Maurice L. Brady ◽

Diem T. Le ◽

Jordon N. Mar ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Atp Production ◽

Primary Substrate

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The Recombinant Fragment of Human κ-Casein Induces Cell Death by Targeting the Proteins of Mitochondrial Import in Breast Cancer Cells

Cancers ◽

10.3390/cancers12061427 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1427

Author(s):

Max Richter ◽

Fabian Wohlfromm ◽

Thilo Kähne ◽

Hannes Bongartz ◽

Kamil Seyrek ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Molecular Mechanisms ◽

Mitochondrial Import ◽

Recombinant Fragment ◽

Atp Production ◽

Interaction Partners ◽

Dimeric Form

Breast cancer is still one of the most common cancers for women. Specified therapeutics are indispensable for optimal treatment. In previous studies, it has been shown that RL2, the recombinant fragment of human κ-Casein, induces cell death in breast cancer cells. However, the molecular mechanisms of RL2-induced cell death remain largely unknown. In this study, mechanisms of RL2-induced cell death in breast cancer cells were systematically investigated. In particular, we demonstrate that RL2 induces loss of mitochondrial membrane potential and cellular ATP loss followed by cell death in breast cancer cells. The mass spectrometry-based screen for RL2 interaction partners identified mitochondrial import protein TOM70 as a target of RL2, which was subsequently validated. Further to this, we show that RL2 is targeted to mitochondria after internalization into the cells, where it can also be found in the dimeric form. The importance of TOM70 and RL2 interaction in RL2-induced reduction in ATP levels was validated by siRNA-induced downregulation of TOM70, resulting in the partial rescue of ATP production. Taken together, this study demonstrates that RL2–TOM70 interaction plays a key role in RL2-mediated cell death and targeting this pathway may provide new therapeutic options for treating breast cancer.

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Abstract P3-04-11: ER is required for mTORC1 inhibitor-induced feedback activation of PI3K/AKT in ER+ breast cancer cells and patients' tumors

10.1158/1538-7445.sabcs16-p3-04-11 ◽

2017 ◽

Author(s):

W Yang ◽

VS Chen ◽

GN Schwartz ◽

JD Marotti ◽

KM Rosenkranz ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Feedback Activation

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Inhibition of mitochondrial pyruvate dehydrogenase kinase: a proposed mechanism by which melatonin causes cancer cells to overcome cytosolic glycolysis, reduce tumor biomass and reverse insensitivity to chemotherapy

Melatonin Research ◽

10.32794/mr11250033 ◽

2019 ◽

Vol 2 (3) ◽

pp. 105-119 ◽

Cited By ~ 19

Author(s):

Russel J Reiter ◽

Ramaswamy Sharma ◽

Qiang Ma ◽

Sergio Rosales-Corral ◽

Dario Acuna-Castroviejo ◽

...

Keyword(s):

Breast Cancer ◽

Oxidative Phosphorylation ◽

Cancer Cells ◽

Pyruvate Dehydrogenase ◽

Warburg Effect ◽

Breast Cancer Cells ◽

Pyruvate Dehydrogenase Kinase ◽

Cell Phenotype ◽

Acetyl Coa ◽

The Warburg Effect

This review presents a hypothesis to explain the role of melatonin in regulating glucose metabolism in cancer cells. Many cancer cells use cytosolic glycolysis (the Warburg effect) to produce energy (ATP). Under these conditions, glucose is primarily converted to lactate which is released into the blood in large quantities. The Warburg effect gives cancer cells advantages in terms of enhanced macromolecule synthesis required for accelerated cellular proliferation, reduced cellular apoptosis which enhances tumor biomass and a greater likelihood of metastasis. Based on available data, high circulating melatonin levels at night serve as a signal for breast cancer cells to switch from cytosolic glycolysis to mitochondrial glucose oxidation and oxidative phosphorylation for ATP production. In this situation, melatonin promotes the synthesis of acetyl-CoA from pyruvate; we speculate that melatonin does this by inhibiting the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) which normally inhibits pyruvate dehydrogenase complex (PDC), the enzyme that controls the pyruvate to acetyl-CoA conversion. Acetyl-CoA has several important functions in the mitochondria; it feeds into the citric acid cycle which improves oxidative phosphorylation and, additionally, it is a necessary co-factor for the rate limiting enzyme, arylalkylamine N-acetyltransferase, in mitochondrial melatonin synthesis. When breast cancer cells are using cytosolic glycolysis (during the day) they are of the cancer phenotype; at night when they are using mitochondria to produce ATP via oxidative phosphorylation, they have a normal cell phenotype. If this day:night difference in tumor cell metabolism is common in other cancers, it indicates that these tumor cells are only cancerous part of the time. We also speculate that high nighttime melatonin levels also reverse the insensitivity of tumors to chemotherapy.

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Hesperidin and Chlorogenic Acid Synergistically Inhibit the Growth of Breast Cancer Cells via Estrogen Receptor/Mitochondrial Pathway

Life ◽

10.3390/life11090950 ◽

2021 ◽

Vol 11 (9) ◽

pp. 950

Author(s):

Pang-Hung Hsu ◽

Wei-Hsuan Chen ◽

Chen JuanLu ◽

Shu-Chen Hsieh ◽

Shih-Chao Lin ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Chlorogenic Acid ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Breast Cancer Patients ◽

Atp Production ◽

Chemotherapy Drugs ◽

Mitochondrial Functions ◽

Mcf 7

Breast cancer is the most common cancer in women worldwide. Hesperidin (Hes) and chlorogenic acid (CA) are traditional medicinal molecules that abundantly exist in natural plants or foods. These compounds have been shown to prevent and suppress various cancers and therefore can be utilized as adjunctive therapies to aid cancer treatment. Here, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays show a greater synergistic inhibitory effect on the growth of breast cancer cells, MCF-7, but not normal breast cells, MCF-10A, than hesperidin or chlorogenic acid alone. We present the possible molecular signaling pathways in MCF-7 cells with or without herbal molecule treatments via proteomic approaches. The data were further analyzed by Ingenuity Pathway Analysis (IPA) and confirmed by quantifying mRNA associated with the estrogen-receptor signaling pathway and mitochondrial functions. We demonstrated that the expression of CYC1, TFAM, ATP5PB, mtATP6, mtDNA, and NRF-1 were decreased upon 12 h treatment, and subsequent ATP production was also significantly decreased at 24 h. These results identified a synergistic effect induced by combinational treatment with hesperidin and chlorogenic acid, which can regulate mitochondria and ATP production through the estrogen receptor pathway in MCF-7 cells. However, none of the treatments induced the generation of reactive oxygen species (ROS), suggesting that ROS likely plays no role in the observed pharmacological activities. Overall, our study sheds light on the adequacy of hesperidin and chlorogenic acid to serve as an adjunctive therapy when co-administrated with chemotherapy drugs in breast cancer patients.

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