Anaplerosis in cancer: Another step beyond the warburg effect

Ochoa-Ruiz, Estefanía; Díaz-Ruiz, Rodrigo

doi:10.4236/ajmb.2012.24031

Cited by 16 publications

(20 citation statements)

References 77 publications

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“…This is consistent with the observation that cancer cells secrete high levels of alanine as a means to dispose of excess nitrogen [36]. Some of the pyruvate produced from glucose may be shunted into anaplerotic reactions, thereby producing α-KG, glutamate, and alanine via alanine transaminase [37]. Thus, 13 C-labeled species of α-KG, glutamate, and alanine may have the potential to arise by exogenous pyruvate contributing to this reaction in a similar manner.…”

Section: Resultssupporting

confidence: 86%

Tumor stroma interaction is mediated by monocarboxylate metabolism

Patel

Ackerstaff

Serganova

et al. 2017

Experimental Cell Research

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Human breast tumors contain significant amounts of stromal cells. There exists strong evidence that these stromal cells support cancer development and progression by altering various pathways (e.g. downregulation of tumor suppressor genes or autocrine signaling loops). Here, we suggest that stromal carcinoma-associated fibroblasts (CAFs), shown to be generated from bone marrow-derived mesenchymal stem cells, may (i) recycle tumor-derived lactate for their own energetic requirements, thereby sparing glucose for neighboring glycolytic tumor cells, and (ii) subsequently secrete surplus energetically and biosynthetically valuable metabolites of lactate oxidation, such as pyruvate, to support tumor growth. Lactate, taken up by stromal CAFs, is converted to pyruvate, which is then utilized by CAFs for energy needs as well as excreted and shared with tumor cells. We have interrogated lactate oxidation in CAFs to determine what metabolites may be secreted, and how they may affect the metabolism and growth of MDA-MB-231 breast cancer cells. We found that CAFs secrete pyruvate as a metabolite of lactate oxidation. Further, we show that pyruvate is converted to lactate to promote glycolysis in MDA-MB-231 cells and helps to control elevated ROS levels in these tumor cells. Finally, we found that inhibiting or interfering with ROS management, using the naturally occurring flavonoid phloretin (found in apple tree leaves), adds to the cytotoxicity of the conventional chemotherapeutic agent doxorubicin. Our work demonstrates that a lactate-pyruvate, reciprocally-supportive metabolic relationship may be operative within the tumor microenvironment (TME) to support tumor growth, and may be a useful drug target.

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Section: Resultssupporting

confidence: 86%

Tumor stroma interaction is mediated by monocarboxylate metabolism

Patel

Ackerstaff

Serganova

et al. 2017

Experimental Cell Research

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“…In addition, the more effective than shPC54 (Supplemental Figure 4B). It is interesting to note that increased PC activity may occur in other unrelated transformed cell lines (3,27). PC knockdown slowed cell growth, again with shPC55 being more effective than shPC54 (Supplemental Figure 4C).…”

Section: Resultsmentioning

confidence: 96%

Pyruvate carboxylase is critical for non–small-cell lung cancer proliferation

Sellers¹,

Fox²,

Bousamra³

et al. 2015

J. Clin. Invest.

443

483

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“…pyruvate carboxylation (Sellers, Fox et al 2015) and glutaminolysis (DeBerardinis and Cheng 2010, Ochoa-Ruiz and Diaz-Ruiz 2012) is expected to be activated in cancer cells due to growth demand, PC activation appeared to be more closely associated with breast cancer cells than enhanced glutaminolysis, as the latter fueled uracil ring synthesis more extensively in HMEC than MCF-7 cells (cf. Table 4).…”

Section: Discussionmentioning

confidence: 99%

Probing the metabolic phenotype of breast cancer cells by multiple tracer stable isotope resolved metabolomics

Lane

Tan

Wang

et al. 2017

Metabolic Engineering

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Breast cancers vary by their origin and specific set of genetic lesions, which gives rise to distinct phenotypes and differential response to targeted and untargeted chemotherapies. To explore the functional differences of different breast cell types, we performed Stable Isotope Resolved Metabolomics (SIRM) studies of one primary breast (HMEC) and three breast cancer cells (MCF-7, MDAMB-231, and ZR75-1) having distinct genotypes and growth characteristics, using 13C6-glucose, 13C-1+2-glucose, 13C5,15N2-Gln, 13C3-glycerol, and 13C8-octanoate as tracers. These tracers were designed to probe the central energy producing and anabolic pathways (glycolysis, pentose phosphate pathway, Krebs Cycle, glutaminolysis, nucleotide synthesis and lipid turnover). We found that glycolysis was not associated with the rate of breast cancer cell proliferation, glutaminolysis did not support lipid synthesis in primary breast or breast cancer cells, but was a major contributor to pyrimidine ring synthesis in all cell types; anaplerotic pyruvate carboxylation was activated in breast cancer versus primary cells. We also found that glucose metabolism in individual breast cancer cell lines differed between in vitro cultures and tumor xenografts, but not the metabolic distinctions between cell lines, which may reflect the influence of tumor architecture/microenvironment.

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Anaplerosis in cancer: Another step beyond the warburg effect

Cited by 16 publications

References 77 publications

Tumor stroma interaction is mediated by monocarboxylate metabolism

Tumor stroma interaction is mediated by monocarboxylate metabolism

Pyruvate carboxylase is critical for non–small-cell lung cancer proliferation

Probing the metabolic phenotype of breast cancer cells by multiple tracer stable isotope resolved metabolomics

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