Is Lactate an Oncometabolite? Evidence Supporting a Role for Lactate in the Regulation of Transcriptional Activity of Cancer-Related Genes in MCF7 Breast Cancer Cells

San-Millán, Iñigo; Julian, Colleen G.; Matarazzo, Christopher J; Martinez, Janel L.; Brooks, George A.

doi:10.3389/fonc.2019.01536

Cited by 76 publications

(78 citation statements)

References 82 publications

(101 reference statements)

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“…Lactate has been shown to alter the transcriptional activity of several key oncogenes, and increased carcinogenesis signaling due to augmented lactate production can serve as one essential purpose of the Warburg effect 31 . Lactate metabolism is particularly relevant for not only the metabolic equilibrium between hypoxic (lactate-generating) and normoxic (lactate-importing) cancer cells 32 but also the polarization of TAMs by hypoxic cancer cells toward a poorly glycolytic M2-like profile 33 - 35 .…”

Section: Discussionmentioning

confidence: 99%

Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17

Zhang¹,

Xu²,

Xu³

et al. 2021

Theranostics

125

103

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Background: Lactate greatly contributes to the regulation of intracellular communication within the tumor microenvironment (TME). However, the role of lactate in pituitary adenoma (PA) invasion is unclear. In this study, we aimed to clarify the effects of lactate on the TME and the effects of TME on PA invasion. Methods: To explore the correlation between TME acidosis and tumor invasion, LDHA and LAMP2 expression levels were quantified in invasive (n = 32) and noninvasive (n = 32) PA samples. The correlation between immune cell infiltration and tumor invasion was evaluated in 64 PAs. Critical chemokine and key signaling pathway components were detected by qPCR, Western blotting, siRNA knockdown, and specific inhibitors. The functional consequences of CCR4 signaling inhibition were evaluated in vitro and in vivo . Results: Lactate was positively associated with PA invasion. Of the 64 PA tissues, invasive PAs were related to high infiltration of M2-like tumor-associated macrophages (TAMs) (P < 0.05). Moreover, lactate secreted from PA cells facilitated M2 polarization via the mTORC2 and ERK signaling pathways, while activated TAMs secreted CCL17 to promote PA invasion via the CCL17/CCR4/mTORC1 axis. According to univariate analysis of clinical data, high CCL17 expression was associated with larger tumor size (P = 0.0438), greater invasion (P = 0.0334), and higher susceptibility to postoperative recurrence (P = 0.0195) in human PAs. Conclusion: This study illustrates the dynamics between PA cells and immune TME in promoting PA invasion via M2 polarization. CCL17 levels in the TME are related to the PA invasiveness and clinical prognosis, and the CCL17/CCR4/mTOCR1 axis may serve as potential therapeutic targets for Pas.

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Section: Discussionmentioning

confidence: 99%

Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17

Zhang¹,

Xu²,

Xu³

et al. 2021

Theranostics

125

103

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“…In a separate study, our group has previously reported in MCF7 that high glucose induced the Warburg effect, as characterized by an increase in lactate secretion, together with increased lactate transporters and reduced oxidative phosphorylation [ 32 ]. Endogenous, glucose-derived lactate may increase transcription of oncogenes and tumour suppressors such as BRCA1 [ 63 ] and may be preferred over glucose by tumour cells for oxidative metabolism [ 64 ]. While these possible independent effects may not be completely accounted for in the current study, spent media was changed every 24 h to avoid accumulation of metabolism by-products such as lactate [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

Glucose Concentration in Cell Culture Medium Influences the BRCA1-Mediated Regulation of the Lipogenic Action of IGF-I in Breast Cancer Cells

Koobotse

Schmidt

Holly

et al. 2020

IJMS

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Hyperglycaemia is a common metabolic alteration associated with breast cancer risk and progression. We have previously reported that BRCA1 restrains metabolic activity and proliferative response to IGF-I anabolic actions in breast cancer cells cultured in high glucose. Here, we evaluated the impact of normal physiological glucose on these tumour suppressive roles of BRCA1. Human breast cancer cells cultured in normal physiological and high glucose were treated with IGF-I (0–500 ng/mL). Cellular responses were evaluated using immunoblotting, co-immunoprecipitation, and cell viability assay. As we previously reported, IGF-I induced ACCA dephosphorylation by reducing the association between BRCA1 and phosphorylated ACCA in high glucose, and upregulated FASN abundance downstream of ACCA. However, these effects were not observed in normal glucose. Normal physiological glucose conditions completely blocked IGF-I-induced ACCA dephosphorylation and FASN upregulation. Co-immunoprecipitation studies showed that normal physiological glucose blocked ACCA dephosphorylation by increasing the association between BRCA1 and phosphorylated ACCA. Compared to high glucose, the proliferative response of breast cancer cells to IGF-I was reduced in normal glucose, whereas no difference was observed in normal mammary epithelial cells. Considering these results collectively, we conclude that normal physiological glucose promotes the novel function of BRCA1 as a metabolic restraint of IGF-I actions. These data suggest that maintaining normal glucose levels may improve BRCA1 function in breast cancer and slow down cancer progression.

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“…Considering the importance of maintaining homeostasis in physiology, the deleterious effect of prolonged, continuous La − accumulation, as occurs in cancer by comparison to the intermittent La − stimulus during exercise, deserves further exploration (San‐Millan et al . 2019).…”

Section: Rationale and Outlinementioning

confidence: 99%

The anaerobic threshold: 50+ years of controversy

Poole

Rossiter

Brooks

et al. 2020

The Journal of Physiology

Self Cite

197

184

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The anaerobic threshold (AT) remains a widely recognized, and contentious, concept in exercise physiology and medicine. As conceived by Karlman Wasserman, the AT coalesced the increase of blood lactate concentration ([La−]), during a progressive exercise test, with an excess pulmonary carbon dioxide output (V̇normalCO2). Its principal tenets were: limiting oxygen (O2) delivery to exercising muscle→increased glycolysis, La− and H+ production→decreased muscle and blood pH→with increased H+ buffered by blood [HCO3−]→increased CO2 release from blood→increased V̇normalCO2 and pulmonary ventilation. This schema stimulated scientific scrutiny which challenged the fundamental premise that muscle anoxia was requisite for increased muscle and blood [La−]. It is now recognized that insufficient O2 is not the primary basis for lactataemia. Increased production and utilization of La− represent the response to increased glycolytic flux elicited by increasing work rate, and determine the oxygen uptake (V̇normalO2) at which La− accumulates in the arterial blood (the lactate threshold; LT). However, the threshold for a sustained non‐oxidative contribution to exercise energetics is the critical power, which occurs at a metabolic rate often far above the LT and separates heavy from very heavy/severe‐intensity exercise. Lactate is now appreciated as a crucial energy source, major gluconeogenic precursor and signalling molecule but there is no ipso facto evidence for muscle dysoxia or anoxia. Non‐invasive estimation of LT using the gas exchange threshold (non‐linear increase of V̇normalCO2 versus V̇normalO2) remains important in exercise training and in the clinic, but its conceptual basis should now be understood in light of lactate shuttle biology.

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Is Lactate an Oncometabolite? Evidence Supporting a Role for Lactate in the Regulation of Transcriptional Activity of Cancer-Related Genes in MCF7 Breast Cancer Cells

Cited by 76 publications

References 82 publications

Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17

Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17

Glucose Concentration in Cell Culture Medium Influences the BRCA1-Mediated Regulation of the Lipogenic Action of IGF-I in Breast Cancer Cells

The anaerobic threshold: 50+ years of controversy

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