Metabolic control analysis of cellular respiration in situ in intraoperational samples of human breast cancer

Käämbre, Tuuli; Chekulayev, Vladimir; Shevchuk, Igor; Karu-Varikmaa, Minna; Timohhina, Natalja; Tepp, Kersti; Bogovskaja, Jelena; Kütner, Riina; Valvere, Vahur; Saks, Valdur

doi:10.1007/s10863-012-9457-9

Cited by 45 publications

(53 citation statements)

References 106 publications

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“…We have previously shown on clinical samples that both human breast cancer (HBC) and human colorectal cancer (HCC) are not purely glycolytic, but these tumors have sustained OXPHOS as a substantial provider of ATP [26–28]. Here, we extend our studies by comparing bioenergetics of HBC and HCC using kinetic methods.…”

Section: Introductionmentioning

confidence: 73%

Mitochondrial Respiration in Human Colorectal and Breast Cancer Clinical Material Is Regulated Differently

Koit

Shevchuk

Ounpuu

et al. 2017

Oxidative Medicine and Cellular Longevity

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We conducted quantitative cellular respiration analysis on samples taken from human breast cancer (HBC) and human colorectal cancer (HCC) patients. Respiratory capacity is not lost as a result of tumor formation and even though, functionally, complex I in HCC was found to be suppressed, it was not evident on the protein level. Additionally, metabolic control analysis was used to quantify the role of components of mitochondrial interactosome. The main rate-controlling steps in HBC are complex IV and adenine nucleotide transporter, but in HCC, complexes I and III. Our kinetic measurements confirmed previous studies that respiratory chain complexes I and III in HBC and HCC can be assembled into supercomplexes with a possible partial addition from the complex IV pool. Therefore, the kinetic method can be a useful addition in studying supercomplexes in cell lines or human samples. In addition, when results from culture cells were compared to those from clinical samples, clear differences were present, but we also detected two different types of mitochondria within clinical HBC samples, possibly linked to two-compartment metabolism. Taken together, our data show that mitochondrial respiration and regulation of mitochondrial membrane permeability have substantial differences between these two cancer types when compared to each other to their adjacent healthy tissue or to respective cell cultures.

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Section: Introductionmentioning

confidence: 73%

Mitochondrial Respiration in Human Colorectal and Breast Cancer Clinical Material Is Regulated Differently

Koit

Shevchuk

Ounpuu

et al. 2017

Oxidative Medicine and Cellular Longevity

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“…Freshly isolated tumor tissue from untreated or AG311-treated mice was prepared for oxygraphic measurements as previously described [28,29]. Tumors from AG311-treated mice were excised 1 hour after intraperitoneal injection with a 45 mg/kg dose.…”

Section: Methodsmentioning

confidence: 99%

AG311, a small molecule inhibitor of complex I and hypoxia-induced HIF-1α stabilization

et al. 2017

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Cancer cells have a unique metabolic profile and mitochondria have been shown to play an important role in chemoresistance, tumor progression and metastases. This unique profile can be exploited by mitochondrial-targeted anticancer therapies. A small anticancer molecule, AG311, was previously shown to possess anticancer and antimetastatic activity in two cancer mouse models and to induce mitochondrial depolarization. This study defines the molecular effects of AG311 on the mitochondria to elucidate its observed efficacy. AG311 was found to competitively inhibit complex I activity at the ubiquinone-binding site. Complex I as a target for AG311 was further established by measuring oxygen consumption rate in tumor tissue isolated from AG311-treated mice. Cotreatment of cells and animals with AG311 and dichloroacetate, a pyruvate dehydrogenase kinase inhibitor that increases oxidative metabolism, resulted in synergistic cell kill and reduced tumor growth. The inhibition of mitochondrial oxygen consumption by AG311 was found to reduce HIF-1α stabilization by increasing oxygen tension in hypoxic conditions. Taken together, these results suggest that AG311 at least partially mediates its antitumor effect through inhibition of complex I, which could be exploited in its use as an anticancer agent.

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“…OXPHOS) was strongly controlled by the 6 evaluated steps: the respiratory chain complexes with flux-control coefficients of 0.44-0.46 for C I; 0.51-0.54 for C III; 0.73 for C IV; of 0.65 for ATP synthase; 1-1.03 for the adenine nucleotide translocator (ANT); and 0.58-0.65 for the Pi carrier [43]. As the sum of the flux-control coefficients was near 4 instead of 1, it was suggested that the natural molecular arrangement of the OXPHOS enzymes in supra-molecular complexes is preserved when intact cells or cells permeabilized with mild detergents are used, whereas the integrity of the supra-molecular complexes is not maintained when isolated mitochondria are studied.…”

Section: Challenges Of the Warburg Effectmentioning

confidence: 99%

Warburg Effect or Reverse Warburg Effect? A Review of Cancer Metabolism

et al. 2015

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Cancer is a major threat to human health. A considerable amount of research has focused on elucidating the nature of cancer from its pathogenesis to treatment and prevention. Tumor cell metabolism has been considered a hallmark of cancer. Cancer cells differ from normal cells through unlimited cell division, and show a greater need for energy for their rapid growth and duplication. Research on glycometabolism, as the key point of energy metabolism, has played a unique role. In the 1920s, Warburg found that cancer cells prefer to produce adenosine triphosphate (ATP) by glycolysis, which is a less efficient pathway compared to oxidative phosphorylation. This striking discovery, called ‘the Warburg effect', has influenced and guided the study of the mechanism and treatment of tumors for generations, but its causal relationship with cancer progression is still unclear. Some studies have now shown contradicting evidence and a new hypothesis, the reverse Warburg effect, has been put forward, in which cancer cells produce most of their ATP via glycolysis, even under aerobic conditions. In this review we discuss the new points concerning the energy metabolism of a tumor, as well as the current facts and perspectives.

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Metabolic control analysis of cellular respiration in situ in intraoperational samples of human breast cancer

Cited by 45 publications

References 106 publications

Mitochondrial Respiration in Human Colorectal and Breast Cancer Clinical Material Is Regulated Differently

Mitochondrial Respiration in Human Colorectal and Breast Cancer Clinical Material Is Regulated Differently

AG311, a small molecule inhibitor of complex I and hypoxia-induced HIF-1α stabilization

Warburg Effect or Reverse Warburg Effect? A Review of Cancer Metabolism

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