Mitochondrial phosphoenolpyruvate carboxykinase promotes tumor growth in estrogen receptor‐positive breast cancer via regulation of the <scp>mTOR</scp> pathway

Hsu, Hui‐Ping; Chu, Pei‐Yi; Chang, Tsung-Ming; Huang, Kuo‐Wei; Hung, Wen‐Chun; Jiang, Shih Sheng; Lin, Hui‐You; Tsai, Hui‐Jen

doi:10.1002/cam4.4969

Cited by 10 publications

(10 citation statements)

References 42 publications

(122 reference statements)

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“…PCK expression is significantly increased in HER2+ cases from our cohort, contradicting previous results. In a study involving 177 breast cancer patients, stratified based on receptor status, a significant association was observed solely with the estrogen receptor and not with HER2 [27]. It was previously described that PCK leads to increased glucose production, promoting hyperglycemia and worsening the diabetes condition [28].…”

Section: Discussionmentioning

confidence: 93%

Breast Cancer Molecular Subtypes Differentially Express Gluconeogenic Rate-Limiting Enzymes—Obesity as a Crucial Player

Luís,

Schmitt,

Fernandes

et al. 2023

Cancers

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Breast cancer is a heterogeneous entity, where different molecular subtypes (MS) exhibit distinct prognostic and therapeutic responses. A series of 62 breast cancer samples stratified by MS was obtained from the tumor biobank of IPO-Porto. The expression of glycolysis and gluconeogenesis-regulating enzymes was investigated by immunohistochemistry. Data analysis included stratification according to MS, body mass index (BMI), and BMI with MS (mBMI). We observed significant differences in pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PCK), and fructose-1,6-bisphosphatase (FBP) tumor cell expression when stratified by MS and mBMI. The expression of these enzymes was also statistically dependent on hormonal receptors and HER2 status and correlated with pathological stage and histological grade. Obesity tended to attenuate these differences, particularly in PC expression, although these were not affected by adipocyte deposition or inflammatory infiltration at the tumor microenvironment. Nonetheless, PCK and FBP expression was also modified by the presence of obesity-associated disorders like diabetes, hypertension, and dyslipidemia. Taken together, these findings identify metabolic fingerprints for breast cancer as distinct histological types, which are affected by the presence of obesity and obesity-associated conditions. Despite the biological role of the differential expression of enzymes remaining unknown, the current study highlights the need to identify the expression of gluconeogenic-regulating enzymes as a tool for personalized medicine.

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Section: Discussionmentioning

confidence: 93%

Breast Cancer Molecular Subtypes Differentially Express Gluconeogenic Rate-Limiting Enzymes—Obesity as a Crucial Player

Luís,

Schmitt,

Fernandes

et al. 2023

Cancers

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“…https://doi.org/10.1038/s42003-024-06186-6 Article proliferation of renal carcinoma cells 58 , whereas PCK2 silencing reduced colony formation of human lung cancer cells 56 and proliferation of breast cancer cell lines 21,59 , but PCK2 inhibition enhanced survival of tumor initiating cells of melanoma 60 , thus illustrating the contextual role of PCK2 in different cell types. Fifth, further supporting the different role of GNG enzymes in cancer cells versus ECs, both cancer cells and ECs utilize GNG enzymes for functions beyond their traditional role in synthesizing glycolytic intermediates, but rely on different GNG enzymes.…”

Section: Discussionmentioning

confidence: 99%

The gluconeogenesis enzyme PCK2 has a non-enzymatic role in proteostasis in endothelial cells

de Zeeuw,

Treps,

García-Caballero

et al. 2024

Commun Biol

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Endothelial cells (ECs) are highly glycolytic, but whether they generate glycolytic intermediates via gluconeogenesis (GNG) in glucose-deprived conditions remains unknown. Here, we report that glucose-deprived ECs upregulate the GNG enzyme PCK2 and rely on a PCK2-dependent truncated GNG, whereby lactate and glutamine are used for the synthesis of lower glycolytic intermediates that enter the serine and glycerophospholipid biosynthesis pathways, which can play key roles in redox homeostasis and phospholipid synthesis, respectively. Unexpectedly, however, even in normal glucose conditions, and independent of its enzymatic activity, PCK2 silencing perturbs proteostasis, beyond its traditional GNG role. Indeed, PCK2-silenced ECs have an impaired unfolded protein response, leading to accumulation of misfolded proteins, which due to defective proteasomes and impaired autophagy, results in the accumulation of protein aggregates in lysosomes and EC demise. Ultimately, loss of PCK2 in ECs impaired vessel sprouting. This study identifies a role for PCK2 in proteostasis beyond GNG.

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“…Oxaloacetate (OAA) is an endogenous metabolic intermediate involved in several metabolic processes, as an example OAA is produced from malic acid catalyzed by malate dehydrogenase, and then OAA is condensed with acetyl coenzyme A to produces citric acid, thus potentially stimulating glycolytic flux and increasing mitochondrial mass ( Hsu et al, 2022 ). OAA is closely related to mitochondrial function.…”

Section: Discussionmentioning

confidence: 99%

Oxaloacetate acid ameliorates paraquat-induced acute lung injury by alleviating oxidative stress and mitochondrial dysfunction

Chen

et al. 2022

Front. Pharmacol.

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Acute lung injury (ALI) is the primary cause of death among patients with acute paraquat (PQ) poisoning, whereby peroxidative damage is an important mechanism underlying PQ-induced lung injury. There is a lack of effective interventional drugs for patients with PQ poisoning. Oxaloacetic acid (OAA) participates in multiple in vivo metabolic processes, whereby it facilitates the clearance of reactive oxygen species (ROS) and improves mitochondrial function. The study aimed to assess the protective effects of OAA on PQ-induced ALI and elucidate the underlying molecular mechanism. Our data demonstrated that OAA treatment significantly alleviated PQ-induced ALI and improved the survival rate of PQ-poisoned mice, and also alleviated PQ-induced cellular oxidative stress and mitochondrial dysfunction. OAA-mediated alleviation of PQ-induced mitochondrial dysfunction depends on the following mechanisms which may explain the above findings: 1) OAA effectively cleared intracellular ROS, inhibited ROS accumulation, and mitochondrial depolarization; 2) OAA inhibited the downregulation of L-OPA1 and MFN2 caused by PQ and promoted a dynamic balance of mitochondrial fusion and fission, and 3) the expression of PGC-1α, TFAM, COX2, and COX4I1, increased significantly following OAA intervention which improved mitochondrial respiratory functions and promoted its biogenesis and energy metabolism in damaged cells. In conclusion, OAA effectively cleared ROS and improved mitochondrial dysfunction, thereby significantly improving ALI caused by PQ poisoning and the animal survival rate. Therefore, OAA may be a potential drug for the treatment of PQ poisoning.

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Mitochondrial phosphoenolpyruvate carboxykinase promotes tumor growth in estrogen receptor‐positive breast cancer via regulation of the mTOR pathway

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 10 publications

References 42 publications

Breast Cancer Molecular Subtypes Differentially Express Gluconeogenic Rate-Limiting Enzymes—Obesity as a Crucial Player

Breast Cancer Molecular Subtypes Differentially Express Gluconeogenic Rate-Limiting Enzymes—Obesity as a Crucial Player

The gluconeogenesis enzyme PCK2 has a non-enzymatic role in proteostasis in endothelial cells

Oxaloacetate acid ameliorates paraquat-induced acute lung injury by alleviating oxidative stress and mitochondrial dysfunction

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