Citrate activates autophagic death of prostate cancer cells via downregulation CaMKII/AKT/mTOR pathway

Fan, Xirui; Zhou, Jinyi; Yan, Xintong; Bi, Xiaowen; Jiang, Liang; Lü, Shuai; Luo, Lan; Zhou, Detang; Yin, Zhimin

doi:10.1016/j.lfs.2021.119355

Cited by 14 publications

(10 citation statements)

References 54 publications

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“…Indeed, citrate provides acetyl-CoA (supporting various processes such as protein acetylation regulating enzyme activities, histone acetylation regulating gene expression, and lipid synthesis required for membrane formation) and also OAA (which can sustain biosynthesis or supply energy through TCA cycle coupled with OXPHOS). In addition, contrary to what was observed in normal cells, in cancer cells, the upregulation of ACLY concurs to maintain a low cytosolic level of citrate, favoring further the enhancement of glycolysis (which would be inhibited by high citrate) and the activation of oncogenic drivers, such as the PI3K/Akt and WNT/β-catenin pathway, which promotes aggressiveness, EMT and de-differentiation [ 77 , 87 , 91 , 144 , 145 , 149 ]. As we have seen, we proposed that the impediment of the negative feedback exercised by citrate on PFK1 and PFK2 is an essential factor of the Warburg effect functioning, allowing high production of F-1,6-BP.…”

Section: Discussion and Therapeutic Perspectivesmentioning

confidence: 99%

“…Of note, this survival process—recycling superfluous molecules (proteins and lipids)—requires functional mitochondria for ATP production derived from FAO [ 157 ]. However, the effects of citrate on PCa are controversial, taking into account that a recent study reported that citrate activates autophagic cell death via downregulation of the Akt/mTOR pathway, also suppressing growth of PCa xenograft tumors in mice [ 145 ]. Additionally, a prolonged inhibition of pmCiC could be bypassed by increasing the uptake of acetate, which is another source of acetyl-CoA [ 158 ], or by producing acetyl-CoA directly from glycolysis through transketolase-like 1 activity [ 159 ].…”

Section: Discussion and Therapeutic Perspectivesmentioning

confidence: 99%

“…For clinical tests, it should be mentioned that citrate has a very low toxicity (see “citrate” PubChem CID 311, at , accessed on 17 June 2021), as confirmed also by in vivo studies [ 145 ], because it is an endogenous metabolite with a complete and rapid metabolism, and thus a very short half-life [ 160 ]. However, if administrated in excess, citrate could cause hypocalcaemia, muscle spasms, convulsions, and also a risk of haemorrhage due to its chelating properties of calcium and other divalent cations.…”

Section: Discussion and Therapeutic Perspectivesmentioning

confidence: 99%

“…Clinical trials should determine the mode and duration of citrate sodium administration, its toxicity, and its efficiency. Knowing that numerous patients worldwide have incurable cancers supported by aerobic glycolysis and key oncogenic drivers (such as IGF-1R, Ras/PI3K/Akt, HER2/neu, WNT/β-catenin, TME acidity and EMT) [ 145 , 161 , 162 ], all pathways efficiently counteracted by citrate sodium in preclinical studies, we strongly believe that the citrate strategy we have proposed since many years [ 25 ] should now be considered for clinical trials. In particular, this strategy could increase both the sensitivity to standard chemotherapy drugs and to targeted therapies, whose resistance is mainly supported by the Warburg effect and its oncogenic drivers.…”

Section: Discussion and Therapeutic Perspectivesmentioning

confidence: 99%

“…Interestingly, plasma citrate levels of these chronically citrate-treated mice were approximately 3 mM, roughly eight times higher than the ones recorded for non-citrate treated mice [ 77 ]. A recent study showed that citrate also suppresses growth of PCa xenograft tumors in mice [ 145 ]. Of note, in a pancreatic cancer-xenograft murine model, 14 daily doses (500 mg/kg/day) of oral citrate induced the neutralization of TME acidity and potentiated the therapeutic effect of an oral administration of active 5-fluoro-uracil derivative [ 146 ].…”

Section: The Anti-cancer Effects Of Citrate At High Dosages In Preclinical Experimentsmentioning

confidence: 99%

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Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update

Icard

Coquerel

et al. 2021

IJMS

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Citrate plays a central role in cancer cells’ metabolism and regulation. Derived from mitochondrial synthesis and/or carboxylation of α-ketoglutarate, it is cleaved by ATP-citrate lyase into acetyl-CoA and oxaloacetate. The rapid turnover of these molecules in proliferative cancer cells maintains a low-level of citrate, precluding its retro-inhibition on glycolytic enzymes. In cancer cells relying on glycolysis, this regulation helps sustain the Warburg effect. In those relying on an oxidative metabolism, fatty acid β-oxidation sustains a high production of citrate, which is still rapidly converted into acetyl-CoA and oxaloacetate, this latter molecule sustaining nucleotide synthesis and gluconeogenesis. Therefore, citrate levels are rarely high in cancer cells. Resistance of cancer cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), is frequently sustained by aerobic glycolysis and its key oncogenic drivers, such as Ras and its downstream effectors MAPK/ERK and PI3K/Akt. Remarkably, in preclinical cancer models, the administration of high doses of citrate showed various anti-cancer effects, such as the inhibition of glycolysis, the promotion of cytotoxic drugs sensibility and apoptosis, the neutralization of extracellular acidity, and the inhibition of tumors growth and of key signalling pathways (in particular, the IGF-1R/AKT pathway). Therefore, these preclinical results support the testing of the citrate strategy in clinical trials to counteract key oncogenic drivers sustaining cancer development and resistance to anti-cancer therapies.

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Section: Discussion and Therapeutic Perspectivesmentioning

confidence: 99%

Section: Discussion and Therapeutic Perspectivesmentioning

confidence: 99%

Section: Discussion and Therapeutic Perspectivesmentioning

confidence: 99%

Section: Discussion and Therapeutic Perspectivesmentioning

confidence: 99%

Section: The Anti-cancer Effects Of Citrate At High Dosages In Preclinical Experimentsmentioning

confidence: 99%

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Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update

Icard

Coquerel

et al. 2021

IJMS

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Thrombin receptor PAR4 cross-activates the tyrosine kinase c-met in atrial cardiomyocytes

Mittendorff,

Abu-Taha,

Kassler

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Thrombin supports coagulation-independent inflammation via protease-activated receptors (PAR). PAR4 is specifically increased in obese human atria, correlating with NLRP3 inflammasome activation. PAR4-mediated NLRP3 inflammasome activation in atrial cardiomyocytes is not known, nor have signaling partners been identified. Thrombin transactivates the hepatocyte growth factor receptor in some cancer cells, so we examined PAR4/c-met cross-talk in atrial cardiomyocytes and its possible significance in obesity. Cardiomyocytes from right atrial appendages (RAA) of obese patients expressed more PAR1 and PAR4 compared to non-obese. In HL-1 atrial cardiomyocytes, thrombin induced caspase-1 auto-activation and IL-1β maturation; IL-1β secretion was evoked by PAR4-activating peptide (AP), but not PAR1-AP. PAR4-AP additionally increased phosphorylated CaMKII-Thr287, mTOR-Ser2481, and Akt-Ser473 while suppressing AMPK-Thr172 phosphorylation. Total kinase levels were largely unaltered. PAR4AP rapidly increased phosphorylated c-met in HL-1 cells and over time also transcriptionally upregulated c-met. The c-met inhibitor SGX-523 abrogated the effects of PAR4-AP on CaMKII/AKT/mTOR phosphorylation but did not affect PAR4-stimulated IL-1β production. Obese human RAA contained more IL-1β, phospho-c-met, and phospho-mTOR than non-obese RAA; CamKII phosphorylation was not modified. Atria from high-fat diet (HFD) versus chow-fed mice also contained more IL-1β, together with higher myeloperoxidase activity, Acta2 mRNA total and phosphorylated c-met; these increases were blunted in PAR4-/- HFD-fed mice. Thrombin cross-activates c-met via PAR4 in atrial cardiomyocytes. Transactivated c-met contributes partially to PAR4-mediated signaling, but NLRP3 inflammasome activation appears to be largely independent of c-met. Abundance of PAR4 and activated c-met increases with obesity, providing therapeutic targets for management of adiposity-driven AF.

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Targeting PI3K/Akt signaling in prostate cancer therapy

Hashemi

Taheriazam

Daneii

et al. 2022

J. Cell Commun. Signal.

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Urological cancers have obtained much attention in recent years due to their mortality and morbidity. The most common and malignant tumor of urological cancers is prostate cancer that imposes high socioeconomic costs on public life and androgen‐deprivation therapy, surgery, and combination of chemotherapy and radiotherapy are employed in its treatment. PI3K/Akt signaling is an oncogenic pathway responsible for migration, proliferation and drug resistance in various cancers. In the present review, the role of PI3K/Akt signaling in prostate cancer progression is highlighted. The activation of PI3K/Akt signaling occurs in prostate cancer, while PTEN as inhibitor of PI3K/Akt shows down‐regulation. Stimulation of PI3K/Akt signaling promotes survival of prostate tumor cells and prevents apoptosis. The cell cycle progression and proliferation rate of prostate tumor cells increase by PI3K/Akt signaling induction. PI3K/Akt signaling stimulates EMT and enhances metastasis of prostate tumor cells. Silencing PI3K/Akt signaling impairs growth and metastasis of prostate tumor cells. Activation of PI3K/Akt signaling mediates drug resistance and reduces radio‐sensitivity of prostate tumor cells. Anti‐tumor compounds suppress PI3K/Akt signaling in impairing prostate tumor progression. Furthermore, upstream regulators such as miRNAs, lncRNAs and circRNAs regulate PI3K/Akt signaling and it has clinical implications for prostate cancer patients.

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Citrate activates autophagic death of prostate cancer cells via downregulation CaMKII/AKT/mTOR pathway

Cited by 14 publications

References 54 publications

Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update

Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update

Thrombin receptor PAR4 cross-activates the tyrosine kinase c-met in atrial cardiomyocytes

Targeting PI3K/Akt signaling in prostate cancer therapy

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