Classical NF-κB Metabolically Reprograms Sarcoma Cells Through Regulation of Hexokinase 2

Londhe, Priya; Yu, Peter Y.; Ijiri, Yuichi; Ladner, Katherine J.; Fenger, Joelle M.; London, Cheryl A.; Houghton, Peter J.; Guttridge, Denis C.

doi:10.3389/fonc.2018.00104

Cited by 54 publications

(46 citation statements)

References 66 publications

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“…39 HK2 is dominantly regulated by various oncogenic pathways, including c-myc, PI3K/ Akt, NF-κB, and HIF-1α. [40][41][42] Our data showed that suppression of Akt signaling was required for sinomenine inhibited HK2 and glycolysis. Ectopically overexpression of constitutively activated Akt1, Myr-Akt1, partly rescued sinomenineinduced glycolysis inhibition and apoptosis induction.…”

Section: Discussionmentioning

confidence: 67%

<p>Sinomenine Inhibits Non-Small Cell Lung Cancer via Downregulation of Hexokinases II-Mediated Aerobic Glycolysis</p>

Liu¹,

Yu²,

Zhou³

et al. 2020

OTT

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These authors contributed equally to this workBackground: Addiction to aerobic glycolysis is a common metabolic phenotype in human non-small cell lung cancer (NSCLC). The natural product Sinomenine (Sin) exhibits significant anti-tumor effects in various human cancers. However, the underlying mechanism remains elusive. Methods: The inhibitory effect of Sin on NSCLC cells was determined by MTS and soft agar assays. The glycolysis efficacy of NSCLC cells was examined by glucose uptake and lactate production. The activation of Akt signaling and the protein level of hexokinases II (HK2) were examined by immunoblot (IB), qRT-PCR, and immunohistochemical staining (IHC). The in vivo anti-tumor effect of Sin was validated by the xenograft mouse model. Results: We showed that HK2 is highly expressed in NSCLC tissues and cell lines. Depletion of HK2 suppressed cell viability, anchorage-independent colony formation, and xenograft tumor growth. Sinomenine exhibited a profound inhibitory effect on NSCLC cells by reducing HK2-mediated glycolysis both in vitro and in vivo. Ectopic overexpression of HK2 compromised these anti-tumor efficacies in sinomenine-treated NSCLC cells. Moreover, we revealed that sinomenine decreased Akt activity, which caused the downregulation of HK2-mediated glycolysis. Knockdown of Akt reduced HK2 protein level and impaired glycolysis. In contrast, overexpression of constitutively activated Akt1 reversed this phenotype. Conclusion: This study suggests that targeting HK2-mediated aerobic glycolysis is required for sinomenine-mediated anti-tumor activity.

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Section: Discussionmentioning

confidence: 67%

<p>Sinomenine Inhibits Non-Small Cell Lung Cancer via Downregulation of Hexokinases II-Mediated Aerobic Glycolysis</p>

Liu¹,

Yu²,

Zhou³

et al. 2020

OTT

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“…In addition, the RNA sequencing data revealed a gene involved in nitrogen metabolism, CPS1, as a potential downstream gene regulated by CARD10. Additionally, the RNA sequencing data revealed several other genes that have been reported to be regulated by the NF‐κB pathway, such as IL6, MAPK1, SSAT, HK2 and GLUT1 . Thus, we hypothesized that CPS1 may also be regulated via the NF‐κB pathway.…”

Section: Discussionmentioning

confidence: 92%

“…Additionally, the RNA sequencing data revealed several other genes that have been reported to be regulated by the NF-κB pathway, such as IL6, MAPK1, SSAT, HK2 and GLUT1. [24][25][26][27][28] Thus, we hypothesized that CPS1 may also be regulated via the NF-κB pathway.…”

Section: Discussionmentioning

confidence: 99%

Caspase recruitment domain family member 10 regulates carbamoyl phosphate synthase 1 and promotes cancer growth in bladder cancer cells

Liu

Zhang

et al. 2019

J Cellular Molecular Medi

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Bladder cancer, which can be divided into non‐muscle‐invasive and muscle‐invasive bladder cancer, is the most common urinary cancer in the United States. Caspase recruitment domain family member 10 (CARD10), also named CARD‐containing MAGUK protein 3 (CARMA3), is a member of the CARMA family and may activate the nuclear factor kappa B (NF‐κB) pathway. We utilized RNA sequencing and metabolic mass spectrometry to identify the molecular and metabolic feature of CARD10. The signalling pathway of CARD10 was verified by Western blotting analysis and functional assays. RNA sequencing and metabolic mass spectrometry of CARD10 knockdown identified the metabolic enzyme carbamoyl phosphate synthase 1 (CPS1) in the urea cycle as the downstream gene regulated by CARD10. We confirmed that CARD10 affected cell proliferation and nucleotide metabolism through regulating CPS1. We indicated that CARD10 promote bladder cancer growth via CPS1 and maybe a potential therapeutic target in bladder cancer.

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“…Thus, NF-κB and MAPK1/2 possess, at least partially, independent roles in TLR9 activation and may be responsible for the metabolic changes seen in CpG-activated MIM −/− B cells. Indeed, NF-κB has been shown to reduce mitochondrial oxidative metabolism in sarcoma cells and MAPK1/2 have been shown to promote glycolytic shift in some cancer types, as well as in rapidly proliferating cells (61,62). This suggests that impaired activation of these modules may underpin the elevated oxidative metabolism in MIM −/− B cells.…”

Section: Discussionmentioning

confidence: 99%

Missing-in-Metastasis/Metastasis Suppressor 1 Regulates B Cell Receptor Signaling, B Cell Metabolic Potential, and T Cell-Independent Immune Responses

et al. 2020

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Efficient generation of antibodies by B cells is one of the prerequisites of protective immunity. B cell activation by cognate antigens via B cell receptors (BCRs), or pathogen-associated molecules through pattern-recognition receptors, such as Toll-like receptors (TLRs), leads to transcriptional and metabolic changes that ultimately transform B cells into antibody-producing plasma cells or memory cells. BCR signaling and a number of steps downstream of it rely on coordinated action of cellular membranes and the actin cytoskeleton, tightly controlled by concerted action of multiple regulatory proteins, some of them exclusive to B cells. Here, we dissect the role of Missing-In-Metastasis (MIM), or Metastasis suppressor 1 (MTSS1), a cancer-associated membrane and actin cytoskeleton regulating protein, in B cell-mediated immunity by taking advantage of MIM knockout mouse strain. We show undisturbed B cell development and largely normal composition of B cell compartments in the periphery. Interestingly, we found that MIM −/− B cells are defected in BCR signaling in response to surface-bound antigens but, on the other hand, show increased metabolic activity after stimulation with LPS or CpG. In vivo, MIM knockout animals exhibit impaired IgM antibody responses to immunization with T cell-independent antigen. This study provides the first comprehensive characterization of MIM in B cells, demonstrates its regulatory role for B cell-mediated immunity, as well as proposes new functions for MIM in tuning receptor signaling and cellular metabolism, processes, which may also contribute to the poorly understood functions of MIM in cancer.

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Classical NF-κB Metabolically Reprograms Sarcoma Cells Through Regulation of Hexokinase 2

Cited by 54 publications

References 66 publications

<p>Sinomenine Inhibits Non-Small Cell Lung Cancer via Downregulation of Hexokinases II-Mediated Aerobic Glycolysis</p>

<p>Sinomenine Inhibits Non-Small Cell Lung Cancer via Downregulation of Hexokinases II-Mediated Aerobic Glycolysis</p>

Caspase recruitment domain family member 10 regulates carbamoyl phosphate synthase 1 and promotes cancer growth in bladder cancer cells

Missing-in-Metastasis/Metastasis Suppressor 1 Regulates B Cell Receptor Signaling, B Cell Metabolic Potential, and T Cell-Independent Immune Responses

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