Lactic Acidosis in Patients with Solid Cancer

Heneberg, Petr

doi:10.1089/ars.2021.0267

Cited by 14 publications

(11 citation statements)

References 229 publications

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“…The observation that PDK4 activity is induced during senescence and plays a critical role in promoting natural aging and contributing to age-related physical dysfunction, underscores this enzyme as a valuable target to counteract the overall pathological impact of senescent cells. Chronological age-associated cellular senescence in the tissue microenvironment bridges the gap between high lactate levels, chronic inflammation and pathological events, while accumulation of lactate in solid organs is a pivotal and early event in various diseases 75,76 . Given that high PDK4 expression rewires energy metabolism, holds the potential to cause tissue homeostasis imbalance and overall physical dysfunction, our study raises the possibility that this metabolic kinase is pharmacologically exploited for therapeutic intervention of natural aging and multiple age-related disorders, including but not limited to cancer.…”

Section: Discussionmentioning

confidence: 99%

Senescent cells develop PDK4-dependent hypercatabolism and produce lactate to promote cancer resistance and aging

Dou

Long

et al. 2023

Preprint

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Senescent cells remain metabolically active, but their metabolic landscape and resulting implications remain underexplored. Here we highlight upregulation of pyruvate dehydrogenase kinase 4 (PDK4) upon cellular senescence, a tendency adversely correlated with cancer patient survival after chemotherapy. Senescent cells exhibit increased aerobic glycolysis and enhanced lactate production, but subject to reversal upon PDK4 inhibition. Distinct from the cancer cell-featured Warburg effect, however, senescent cells sustain mitochondrial respiration and redox activity, adopting a special form of metabolic reprogramming. Media from PDK4+ stromal cells change global expression and promote malignancy of recipient cancer cells in vitro, while targeting PDK4 causes tumor regression in vivo. The metabolite lactate causes NOX1 upregulation and ROS production in mitochondrion-disabled cells, whereas PDK4 suppression reduces DNA damage severity and restrains the senescence-associated secretory phenotype (SASP). In preclinical trials, PDK4 intervention alleviates physical dysfunction and prevents age-associated frailty, conditions frequently observed in advanced life. Together, our study substantiates the hypercatabolic nature of senescent cells, and reveals a metabolic link between cellular senescence, lactate production, chronological aging and age-related pathologies including but not limited to cancer.

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Section: Discussionmentioning

confidence: 99%

Senescent cells develop PDK4-dependent hypercatabolism and produce lactate to promote cancer resistance and aging

Dou

Long

et al. 2023

Preprint

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show abstract

“…The observation that PDK4 activity is induced during senescence and plays a critical role in forming an acidic microenvironment underscores this enzyme as a valuable target to counteract the overall pathological impact of senescent cells. As of note, acidic microenvironments bridge the gap between high lactate levels, chronic inflammation and pathological events, while accumulation of lactate in solid organs is a pivotal and early event in various diseases 65, 66 . Given that high PDK4 expression causes PDH phosphorylation, rewires energy metabolism, holds the potential to drive tissue homeostasis imbalance and physical dysfunction, our study raises the possibility that this metabolic kinase is pharmacologically exploited for therapeutic intervention of aging and multiple age-related disorders, including but not limited to cancer.…”

Section: Discussionmentioning

confidence: 99%

Senescent cells develop PDK4-dependent hypercatabolism and form an acidic microenvironment to drive cancer resistance

Dou

Long

Liu

et al. 2022

Preprint

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Cellular senescence is a state of stable growth arrest, usually accompanied by development of the senescence-associated secretory phenotype (SASP). Although senescent cells remain metabolically active, little is known about their metabolic landscape and in vivo pathophysiological implications. Here we show that expression of the pyruvate dehydrogenase (PDH) inhibitory enzyme, pyruvate dehydrogenase kinase 4 (PDK4), is significantly upregulated in human senescent stromal cells. Preferentially expressed upon genotoxicity-induced senescence (GIS), PDK4 is negatively correlated with posttreatment survival of cancer patients. Upon cellular senescence, PDK4 shifts glucose metabolic flux from oxidative phosphorylation to aerobic glycolysis, causing enhanced lactate production and forming an acidic microenvironment. However, distinct from the cancer cell-featured Warburg effect, senescent cells maintain an intensive use of pyruvate through the tricarboxylic acid cycle (TCA), displaying increased respiration and redox activity, indicative of a special form of metabolic reprogramming. Conditioned media from PDK4+ stromal cells change global expression and promote malignancy of recipient cancer cells in vitro and accelerate tumor progression in vivo. Pharmacologically targeting PDK4 restrains the adverse effects of PDK4 in cell-based assays, while promoting tumor regression and extending posttreatment survival in preclinical trials. Together, our study substantiates the hypercatabolic nature of senescent cells, and reveals a metabolic link between senescence-associated acidic microenvironment and age-related pathologies including but not limited to cancer.

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“…The evidence regarding increased circulating lactate levels in oncological patients is mainly derived from published case reports [121]. In particular, eleven cases from ten papers reporting lactic acidosis in BC patients were retrieved from our search (Table 2) [122][123][124][125][126][127][128][129][130][131].…”

Section: Circulating Lactate In Breast Cancermentioning

confidence: 99%

The Significance of Microenvironmental and Circulating Lactate in Breast Cancer

Frisardi,

Canovi,

Vaccaro

et al. 2023

IJMS

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Lactate represents the main product of pyruvate reduction catalyzed by the lactic dehydrogenase family of enzymes. Cancer cells utilize great quantities of glucose, shifting toward a glycolytic metabolism. With the contribution of tumor stromal cells and under hypoxic conditions, this leads toward the acidification of the extracellular matrix. The ability to shift between different metabolic pathways is a characteristic of breast cancer cells and is associated with an aggressive phenotype. Furthermore, the preliminary scientific evidence concerning the levels of circulating lactate in breast cancer points toward a correlation between hyperlactacidemia and poor prognosis, even though no clear linkage has been demonstrated. Overall, lactate may represent a promising metabolic target that needs to be investigated in breast cancer.

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Lactic Acidosis in Patients with Solid Cancer

Cited by 14 publications

References 229 publications

Senescent cells develop PDK4-dependent hypercatabolism and produce lactate to promote cancer resistance and aging

Senescent cells develop PDK4-dependent hypercatabolism and produce lactate to promote cancer resistance and aging

Senescent cells develop PDK4-dependent hypercatabolism and form an acidic microenvironment to drive cancer resistance

The Significance of Microenvironmental and Circulating Lactate in Breast Cancer

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