Cancer-derived extracellular succinate: a driver of cancer metastasis

Kuo, Cheng-Chin; Wu, Jing-Yiing; Wu, Kenneth K.

doi:10.1186/s12929-022-00878-z

Cited by 29 publications

(24 citation statements)

References 109 publications

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“…The extracellular accumulation of oncogenic signaling molecules, such as succinate, fuel the initiation and progression of carcinogenesis 41,42 . Both host cells and gut bacteria produce succinate; however, in the intestinal lumen succinate is chiefly derived from bacterial metabolism 43 .…”

Section: Resultsmentioning

confidence: 99%

Refined fiber inulin promotes inflammation‐associated colon tumorigenesis by modulating microbial succinate production

Tian,

Paudel,

Hao

et al. 2023

Cancer Reports

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Background and AimThere is an increased risk of colon cancer associated with inflammatory bowel disease (IBD). Dietary fibers (DFs) naturally present in vegetables and whole grains offer numerous beneficial effects on intestinal health. However, the effects of refined DFs on intestinal health remain unclear. Therefore, we elucidated the impact of the refined DF inulin on colonic inflammation and tumorigenesis.MethodsFour‐week‐old wild‐type (WT) mice were fed diets containing insoluble DF cellulose (control) or refined DF inulin for 4 weeks. A subgroup of mice was then switched to drinking water containing dextran sulfate sodium (DSS, 1.4% wt/vol) for colitis induction. In another subgroup of mice, colitis‐associated colorectal cancer (CRC) was initiated with three 7‐day alternate cycles of DSS following an initial dose of mutagenic substance azoxymethane (AOM; 7.5 mg/kg body weight; i.p.). Post 7 weeks of AOM treatment, mice were euthanized and examined for CRC development.ResultsMice consuming inulin‐containing diet exhibited severe colitis upon DSS administration, as evidenced by more body weight loss, rectal bleeding, and increased colonic inflammation than the DSS‐treated control group. Correspondingly, histological analysis revealed extensive disruption of colon architecture and massive infiltration of immune cells in the inulin‐fed group. We next examined the effect of inulin on CRC development. Surprisingly, significant mortality (~50%) was observed in the inulin‐fed but not in the control group during the DSS cycle. Consequently, the remaining inulin‐fed mice, which completed the study exhibited extensive colon tumorigenesis. Immunohistochemical characterization showed comparatively high expression of the cell proliferation marker Ki67 and activation of the Wnt signaling in tumor sections obtained from the inulin‐fed group. Gut microbiota and metabolite analysis revealed expansion of succinate producers and elevated cecal succinate in inulin‐fed mice. Human colorectal carcinoma cells (HCT116) proliferated more rapidly when supplemented with succinate in an inflamed environment, suggesting that elevated luminal succinate may contribute to tumorigenesis.ConclusionsOur study uncovers that supplementation of diet with refined inulin induces abnormal succinate accumulation in the intestinal lumen, which in part contributes to promoting colon inflammation and tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

Refined fiber inulin promotes inflammation‐associated colon tumorigenesis by modulating microbial succinate production

Tian,

Paudel,

Hao

et al. 2023

Cancer Reports

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“…SDH catalyzes the conversion of succinate to fumarate in the TCA cycle, while also facilitating electron transfer, thus promoting respiratory chain activity [ 46 , 53 ]. SDHB is a secondary electron transfer subunit that tightly binds to SDHA and interacts with SDHC and SDHD to form a stable subunit complex [ 54 , 55 ]. Additionally, succinate, an inflammatory metabolite, accumulates during macrophage activation and affects HIF1α activity [ 50 ] and ROS levels [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Fluorinated hydroxyapatite conditions a favorable osteo-immune microenvironment via triggering metabolic shift from glycolysis to oxidative phosphorylation

Chen,

Ha,

et al. 2024

J Transl Med

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Background Biological-derived hydroxyapatite is widely used as a bone substitute for addressing bone defects, but its limited osteoconductive properties necessitate further improvement. The osteo-immunomodulatory properties hold crucial promise in maintaining bone homeostasis, and precise modulation of macrophage polarization is essential in this process. Metabolism serves as a guiding force for immunity, and fluoride modification represents a promising strategy for modulating the osteoimmunological environment by regulating immunometabolism. In this context, we synthesized fluorinated porcine hydroxyapatite (FPHA), and has demonstrated its enhanced biological properties and osteogenic capacity. However, it remains unknown whether and how FPHA affects the immune microenvironment of the bone defects. Methods FPHA was synthesized and its composition and structural properties were confirmed. Macrophages were cultured with FPHA extract to investigate the effects of FPHA on their polarization and the related osteo-immune microenvironment. Furthermore, total RNA of these macrophages was extracted, and RNA-seq analysis was performed to explore the underlying mechanisms associated with the observed changes in macrophages. The metabolic states were evaluated with a Seahorse analyzer. Additionally, immunohistochemical staining was performed to evaluate the macrophages response after implantation of the novel bone substitutes in critical size calvarial defects in SD rats. Results The incorporation of fluoride ions in FPHA was validated. FPHA promoted macrophage proliferation and enhanced the expression of M2 markers while suppressing the expression of M1 markers. Additionally, FPHA inhibited the expression of inflammatory factors and upregulated the expression of osteogenic factors, thereby enhancing the osteogenic differentiation capacity of the rBMSCs. RNA-seq analysis suggested that the polarization-regulating function of FPHA may be related to changes in cellular metabolism. Further experiments confirmed that FPHA enhanced mitochondrial function and promoted the metabolic shift of macrophages from glycolysis to oxidative phosphorylation. Moreover, in vivo experiments validated the above results in the calvarial defect model in SD rats. Conclusion In summary, our study reveals that FPHA induces a metabolic shift in macrophages from glycolysis to oxidative phosphorylation. This shift leads to an increased tendency toward M2 polarization in macrophages, consequently creating a favorable osteo-immune microenvironment. These findings provide valuable insights into the impact of incorporating an appropriate concentration of fluoride on immunometabolism and macrophage mitochondrial function, which have important implications for the development of fluoride-modified immunometabolism-based bone regenerative biomaterials and the clinical application of FPHA or other fluoride-containing materials. Graphical Abstract. FPHA was successfully prepared through the chemical and thermal process. The immunomodulatory effects of FPHA were investigated through in vitro and in vivo studies, revealing its ability to induce a metabolic shift in macrophages from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This metabolic remodeling resulted in a notable suppression of M1 macrophage polarization and promotion of M2 macrophage polarization. Furthermore, FPHA was found to enhance osteogenic differentiation and facilitate bone repair. These findings underscore the promising potential of FPHA as a biomaterial for bone regenerative applications, providing valuable insights for the development of bioactive materials with metabolic-immunoregulatory properties Graphical Abstract

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“…Succinate, an archetypal respiratory substrate, performs many functions other than energy metabolism and could act as a signal biomarker similar to hormones and cytokines, which have been involved in many serious diseases in recent years. [27][28][29][30] In white adipose tissue, succinate binds to its receptor SUCNR1 and acts as a lipolysis inhibitor, thereby exacerbating the accumulation of lipids. 28 Based on the dose-dependent increase in succinate, the succinate-SUCNR1 axis may play an important role in lipid accumulation induced by combined exposure to BPA and fructose.…”

Section: Discussionmentioning

confidence: 99%

Impact of combined chronic exposure to low-dose bisphenol A and fructose on serum adipocytokines and the energy target metabolome in white adipose tissue

Liu,

Li,

Zhong

et al. 2023

Hum Exp Toxicol

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Background: Adipose tissue is a dynamic endocrine organ that plays a key role in regulating metabolic homeostasis. Previous studies confirmed that bisphenol A (BPA) or fructose can interfere with the function of adipose tissue. Nonetheless, knowledge on how exposure to BPA and fructose impacts energy metabolism in adipose tissue remains limited. Purpose: To determine impact of combined chronic exposure to low-dose bisphenol A and fructose on serum adipocytokines and the energy target metabolome in white adipose tissue. Method: 57 energy metabolic intermediates in adipose tissue and 7 adipocytokines in serum from Sprague Dawley rats were examined after combined exposure to two levels of BPA (lower dose: 0.25, and higher dose: 25 μg/kg every other day) and 5% fructose for 6 months. Results: combined exposure to lower-dose BPA and fructose significantly increased omentin-1, pyruvic acid, adenosine triphosphate (ATP), adenosine monophosphate (AMP), inosine monophosphate (IMP), inosine, and l-lactate; however, these parameters were not significantly affected by higher-dose BPA combined with fructose. Interestingly, the level of succinate (an intermediate of the citric acid cycle) increased dose-dependently in adipose tissue, and the level of apelin 13 (a versatile adipocytokine) decreased dose-dependently in serum after combined exposure to BPA and fructose. Phosphoenolpyruvic acid, phenyl-lactate, and ornithine were significantly correlated with asprosin, omentin-1, apelin, apelin 13, and adiponectin, while l-tyrosine was significantly correlated with irisin and a-FABP under combined exposure to BPA and fructose. Conclusions: these findings indicated that lower-dose BPA combined with fructose could amplify the impact on glycolysis, energy storage, and purine nucleotide biosynthesis in adipose tissue, and adipocytokines, such as omentin-1 and apelin 13, may be related to metabolic interference induced by BPA and fructose exposure.

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Cancer-derived extracellular succinate: a driver of cancer metastasis

Cited by 29 publications

References 109 publications

Refined fiber inulin promotes inflammation‐associated colon tumorigenesis by modulating microbial succinate production

Refined fiber inulin promotes inflammation‐associated colon tumorigenesis by modulating microbial succinate production

Fluorinated hydroxyapatite conditions a favorable osteo-immune microenvironment via triggering metabolic shift from glycolysis to oxidative phosphorylation

Impact of combined chronic exposure to low-dose bisphenol A and fructose on serum adipocytokines and the energy target metabolome in white adipose tissue

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