Natural products and other inhibitors of F1FO ATP synthase

Patel, Bhargav A.; D’Amico, Terin; Blagg, Brian S. J.

doi:10.1016/j.ejmech.2020.112779

Cited by 24 publications

(27 citation statements)

References 186 publications

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“…Oligomycin is an inhibitor of F0/F1 adenosine triphosphate (ATP) synthase and mitochondrial respiration, which has been reported to suppress tumour growth 34 . Since SGC707 elicited an effect on suppressing PRMT3‐enhanced HCC glycolysis and growth, we wondered whether combination SGC707 with oligomycin could exhibit a more significant growth‐suppressive effect.…”

Section: Resultsmentioning

confidence: 99%

Protein arginine methyltransferase 3 promotes glycolysis and hepatocellular carcinoma growth by enhancing arginine methylation of lactate dehydrogenase A

Han

et al. 2022

Clinical & Translational Med

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Background Protein arginine methylation has emerged a pivotal role in cancer progression. However, the role of protein arginine methyltransferase 3 (PRMT3) in hepatocellular carcinoma (HCC) remains unknown. Methods The expression pattern of PRMT3 in HCC was analysed using quantitative real‐time‐polymerase chain reaction (qRT‐PCR), Western blotting and immunohistochemistry assays. Loss‐ and gain‐of‐function experiments were carried out to determine the oncogenic role of PRMT3 in HCC. Glucose consumption and lactate production assays, seahorse bioscience, mass spectrometry, co‐immunoprecipitation, metabonomic analysis and site‐specific mutation experiments were used to explore the underlying molecular mechanisms. Furthermore, a xenograft mouse model was established to investigate the effects of PRMT3 and its inhibitor, SGC707, treatment on tumour growth in vivo. Results The expression of PRMT3 was significantly upregulated in HCC, with high expression of which correlated with poor prognosis. PRMT3 knockdown led to the decrease in proliferation, glycolysis of HCC cells and tumour growth, whilst its overexpression showed opposite results. The catalytic activity of PRMT3 was important in mediating these biological processes. Mechanistically, our data showed that PRMT3 interacted with and mediated asymmetric dimethylarginine (ADMA) modification of lactate dehydrogenase A (LDHA) at arginine 112 (R112). Compared with LDHA‐wild‐type (LDHA‐WT) cells, LDHA‐R112K‐mutant‐expressing HCC cells exhibited a decrease in lactate dehydrogenase (LDH) activity, HCC cell glycolysis and proliferation. Furthermore, the administration of SGC707, a selective inhibitor of PRMT3, disrupted the PRMT3‐mediated LDHA methylation and abolished PRMT3‐induced HCC glycolysis and tumour growth. Conclusions Our results suggested a novel oncogenic role of PRMT3 in HCC, and it could be a promising therapeutic target for HCC by linking post‐translational modification and cancer metabolism.

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Section: Resultsmentioning

confidence: 99%

Protein arginine methyltransferase 3 promotes glycolysis and hepatocellular carcinoma growth by enhancing arginine methylation of lactate dehydrogenase A

Han

et al. 2022

Clinical & Translational Med

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“…Patel et al. 47 provided an update on recently discovered ATP synthase modulators. A more comprehensive view of ATP synthase-targeting inhibitors was covered in their study.…”

Section: Discussionmentioning

confidence: 99%

“…Given the role of ATP synthase in fueling cancer, ATP synthase inhibitors have been explored as a new cancer therapy. 44 , 45 Categories that have been developed and investigated are polyketide inhibitors, polyphenolic phytochemicals, estrogens, polyenic α-pyrone derivatives, synthetic compounds, and protein peptides, 46 , 47 some of which were earlier used as antibiotics to treat infectious diseases or anti-obesity drugs and later showed antiangiogenetic and anticancer activity. 48 , 49 , 50 …”

Section: Cancer Therapy Based On Targeting Atp Synthasementioning

confidence: 99%

Defueling the cancer: ATP synthase as an emerging target in cancer therapy

Wang

Qian

2021

Molecular Therapy - Oncolytics

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Reprogramming of cellular metabolism is a hallmark of cancer. Mitochondrial ATP synthase (MAS) produces most of the ATP that drives the cell. High expression of the MAS-composing proteins is found during cancer and is linked to a poor prognosis in glioblastoma, ovarian cancer, prostate cancer, breast cancer, and clear cell renal cell carcinoma. Cell surface-expressed ATP synthase, translocated from mitochondrion to cell membrane, involves the angiogenesis, tumorigenesis, and metastasis of cancer. ATP synthase has therefore been considered a therapeutic target. We review recent various ATP synthase inhibitors that suppress tumor growth and are being tested for the clinic.

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“…( 32 ) A subsequent increase in mitochondrial and cellular ADP should be balanced by concomitant inhibition of ecto‐ATP synthase by resveratrol (⑪b in Fig. 6) ( 33 ) with reduced extracellular ADP formation.…”

Section: Discussionmentioning

confidence: 99%

Adenosine Diphosphate and the P2Y13 Receptor Are Involved in the Autophagic Protection of Ex Vivo Perfused Livers From Fasted Rats: Potential Benefit for Liver Graft Preservation

et al. 2021

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Studies on how to protect livers perfused ex vivo can help design strategies for hepatoprotection and liver graft preservation. The protection of livers isolated from 24-hour versus 18-hour starved rats has been previously attributed to autophagy, which contributes to the energy-mobilizing capacity ex vivo. Here, we explored the signaling pathways responsible for this protection. In our experimental models, 3 major signaling candidates were considered in view of their abilities to trigger autophagy: high mobility group box 1 (HMGB1), adenosine monophosphate-activated protein kinase (AMPK), and purinergic receptor P2Y13. To this end, ex vivo livers isolated from starved rats were perfused for 135 minutes, after which perfusate samples were studied for protein release and biopsies were performed for evaluating signaling protein contents. For HMGB1, no significant difference was observed between livers isolated from rats starved for 18 and 24 hours at perfusion times of both 0 and 135 minutes. The phosphorylated and total forms of AMPK, but not their ratios, were significantly higher in 24-hour fasted than in 18-hour fasted livers. However, although the level of phosphorylated AMPK increased, perfusing ex vivo 18-hour fasted livers with 1 mM 5-aminoimidazole-4-carboxamide ribonucleotide, an AMPK activator, did not protect the livers. In addition, the adenosine diphosphate (ADP; and not adenosine monophosphate [AMP]) to AMP + ADP + adenosine triphosphate ratio increased in the 24-hour starved livers compared with that in the 18-hour starved livers. Moreover, perfusing 24-hour starved livers with 0.1 mM 2-[(2-chloro-5-nitrophenyl)azo]-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]-4-pyridinecarboxaldehyde (MRS2211), a specific antagonist of the P2Y13 receptor, induced an increase in cytolysis marker levels in the perfusate samples and a decrease in the levels of autophagic marker microtubule-associated proteins 1 light chain 3 II (LC3II)/actin (and a loss of p62/actin decrease), indicating autophagy inhibition and a loss of protection. The P2Y13 receptor and ADP (a physiological activator of this receptor) are involved in the protection of ex vivo livers. Therapeutic opportunities for improving liver graft preservation through the stimulation of the ADP/P2Y13 receptor axis are further discussed.

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Natural products and other inhibitors of F1FO ATP synthase

Cited by 24 publications

References 186 publications

Protein arginine methyltransferase 3 promotes glycolysis and hepatocellular carcinoma growth by enhancing arginine methylation of lactate dehydrogenase A

Protein arginine methyltransferase 3 promotes glycolysis and hepatocellular carcinoma growth by enhancing arginine methylation of lactate dehydrogenase A

Defueling the cancer: ATP synthase as an emerging target in cancer therapy

Adenosine Diphosphate and the P2Y13 Receptor Are Involved in the Autophagic Protection of Ex Vivo Perfused Livers From Fasted Rats: Potential Benefit for Liver Graft Preservation

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