Background and Aims Most tumor cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and promote tumorigenicity and drug resistance. Intriguingly, the molecular mechanisms underlying this phenomenon are not well understood. In this work, using gain‐of‐function and loss‐of‐function in vitro studies in patient‐derived organoid and cell cultures as well as in vivo positron emission tomography–magnetic resonance imaging animal models, we showed that protein arginine N‐methyltransferase 6 (PRMT6) regulates aerobic glycolysis in human hepatocellular carcinoma (HCC) through nuclear relocalization of pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect. Approach and Results We found PRMT6 to methylate CRAF at arginine 100, interfering with its RAS/RAF binding potential, and therefore altering extracellular signal–regulated kinase (ERK)‐mediated PKM2 translocation into the nucleus. This altered PRMT6‐ERK‐PKM2 signaling axis was further confirmed in both a HCC mouse model with endogenous knockout of PRMT6 as well as in HCC clinical samples. We also identified PRMT6 as a target of hypoxia through the transcriptional repressor element 1‐silencing transcription factor, linking PRMT6 with hypoxia in driving glycolytic events. Finally, we showed as a proof of concept the therapeutic potential of using 2‐deoxyglucose, a glycolysis inhibitor, to reverse tumorigenicity and sorafenib resistance mediated by PRMT6 deficiency in HCC. Conclusions Our findings indicate that the PRMT6‐ERK‐PKM2 regulatory axis is an important determinant of the Warburg effect in tumor cells, and provide a mechanistic link among tumorigenicity, sorafenib resistance, and glucose metabolism.
Targeting of poly(ADP-ribose)polymerase (PARP) enzymes has emerged as an effective therapeutic strategy to selectively target cancer cells with deficiencies in homologous recombination (HR) signaling. Currently used to treat BRCA-mutated cancers, PARP inhibitors (PARPi) have demonstrated improved outcome in various cancer types as single agents. Ongoing efforts have seen the exploitation of PARPi combination therapies, boosting patient responses as a result of drug synergisms.Despite great successes using PARPi therapy, selecting those patients who will benefit from single agent or combination therapy remains one of the major challenges.Numerous reports have demonstrated that the presence of a BRCA mutation does not always result in synthetic lethality with PARPi therapy in treatment-naïve tumors.Cancer cells can also develop resistance to PARPi therapy. Hence, combination therapy may significantly affect the treatment outcomes. In this review, we discuss the development and utilization of PARPi in different cancer types from preclinical models to clinical trials, provide a current overview of the potential uses of PARP imaging agents in cancer therapy, and discuss the use of radiolabeled PARPi as radionuclide therapies.
The synthesis, isolation and crystallographic characterization of the first N-heterocyclic carbene adducts of bismuth is reported, by direct reaction of the Dipp2NHC (Dipp = 2,6-diisopropylphenyl) or (i)Pr2(Me2)NHC with BiCl3. This represents the last non-radioactive element from groups 13-17 for which an NHC-element fragment remained unreported.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.