Anti-Warburg effect by targeting HRD1-PFKP pathway may inhibit breast cancer progression

Fan, Ya; Wang, Jia; Xu, Yang; Wang, Yipin; Song, Tao; Jin, Feng; Su, Dongming

doi:10.1186/s12964-020-00679-7

Cited by 13 publications

(5 citation statements)

References 29 publications

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“…It is well established that E3 ligases, including SYVN1 can have opposite effects as either tumor suppressors (TS) or oncogenes depending on the context or type of cancer ( 73 – 75 ). With regards to SYVN1, previous studies have shown that it functions as a tumor suppressor in breast ( 37 , 39 , 41 , 76 , 77 ) and ovarian ( 40 ) cancers. On the contrary, the tumor-promoting (oncogenic) effects of SYVN1 have been revealed in colon cancer ( 78 ), lung cancer ( 79 , 80 ), and hepatocellular carcinoma ( 81 , 82 ).…”

Section: Discussionmentioning

confidence: 99%

VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2

Thankan,

Thomas,

Purushottamachar

et al. 2023

Front. Oncol.

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Triple-negative breast cancer (TNBC) and its recently identified subtype, quadruple negative breast cancer (QNBC), collectively account for approximately 13% of reported breast cancer cases in the United States. These aggressive forms of breast cancer are associated with poor prognoses, limited treatment options, and lower overall survival rates. In previous studies, our research demonstrated that VNLG-152R exhibits inhibitory effects on TNBC cells both in vitro and in vivo and the deuterated analogs were more potent inhibitors of TNBC cells in vitro. Building upon these findings, our current study delves into the molecular mechanisms underlying this inhibitory action. Through transcriptome and proteome analyses, we discovered that VNLG-152R upregulates the expression of E3 ligase Synoviolin 1 (SYVN1), also called 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) in TNBC cells. Moreover, we provide genetic and pharmacological evidence to demonstrate that SYVN1 mediates the ubiquitination and subsequent proteasomal degradation of MNK1/2, the only known kinases responsible for phosphorylating eIF4E. Phosphorylation of eIF4E being a rate-limiting step in the formation of the eIF4F translation initiation complex, the degradation of MNK1/2 by VNLG-152R and its analogs impedes dysregulated translation in TNBC cells, resulting in the inhibition of tumor growth. Importantly, our findings were validated in vivo using TNBC xenograft models derived from MDA-MB-231, MDA-MB-468, and MDA-MB-453 cell lines, representing different racial origins and genetic backgrounds. These xenograft models, which encompass TNBCs with varying androgen receptor (AR) expression levels, were effectively inhibited by oral administration of VNLG-152R and its deuterated analogs in NRG mice. Importantly, in direct comparison, our compounds are more effective than enzalutamide and docetaxel in achieving tumor growth inhibition/repression in the AR+ MDA-MD-453 xenograft model in mice. Collectively, our study sheds light on the involvement of SYVN1 E3 ligase in the VNLG-152R-induced degradation of MNK1/2 and the therapeutic potential of VNLG-152R and its more potent deuterated analogs as promising agents for the treatment of TNBC across diverse patient populations.

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Section: Discussionmentioning

confidence: 99%

VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2

Thankan,

Thomas,

Purushottamachar

et al. 2023

Front. Oncol.

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“…45 In addition, the E3 ubiquitin ligase of HRD1 (HMG-CoA reductase degradation 1) was also reported to mediate PFKP ubiquitination and degradation. 46 However, such a mechanism has never been described in PFKM. Our study first demonstrated that the stability of both PFKP and PFKM can be regulated by the TRIM21-mediated ubiquitylation; second, we found that PFKP/M interact with MFN2 via MFN2 C-terminus and the interaction facilitates PFKP/M binding to TRIM21; third, by employing the mechanical stretching experiment, we discovered that the PFKP/M-MFN2 interaction as well as PFKP/M ubiquitylation and stability are mechanically regulated; fourth, study by restoring PFKP expression in MFN2 over-expressing VSMCs, and PFK inhibition in the MFN2 knockdown cells demonstrated the functional interaction between MFN2 and PFK activities.…”

Section: Discussionmentioning

confidence: 99%

MFN2 Prevents Neointimal Hyperplasia in Vein Grafts via Destabilizing PFK1

Tang

Jia

Fan

et al. 2022

Circulation Research

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BACKGROUND: Mechanical forces play crucial roles in neointimal hyperplasia after vein grafting; yet, our understanding of their influences on vascular smooth muscle cell (VSMC) activation remains rudimentary. METHODS: A cuff mouse model was used to study vein graft hyperplasia. Fifteen percent to 1 Hz uniaxial cyclic stretch (arterial strain), 5% to 1 Hz uniaxial cyclic stretch or a static condition (venous strain) were applied to the cultured VSMCs. Metabolomics analysis, cell proliferation and migration assays, immunoblotting, co-immunoprecipitation, mutagenesis, pull-down and surface plasmon resonance assays were employed to elucidate the potential molecular mechanisms. RESULTS: RNA-sequencing in vein grafts and the controls identified changes in metabolic pathways and downregulation of mitochondrial protein MFN2 (mitofusin 2) in the vein grafts. Exposure of VSMCs to 15% stretch resulted in MFN2 downregulation, mitochondrial fragmentation, metabolic shift from mitochondrial oxidative phosphorylation to glycolysis, and cell proliferation and migration, as compared with that to a static condition or 5% stretch. Metabolomics analysis indicated an increased generation of fructose 1,6-bisphosphate, an intermediate in the glycolytic pathway converted by PFK1 (phosphofructokinase 1) from fructose-6-phosphate, in cells exposed to 15% stretch. Mechanistic study revealed that MFN2 physically interacts through its C-terminus with PFK1. MFN2 knockdown or exposure of cells to 15% stretch promoted stabilization of PFK1, likely through interfering the association between PFK1 and the E3 ubiquitin ligase TRIM21 (E3 ubiquitin ligase tripartite motif [TRIM]-containing protein 21), thus, decreasing the ubiquitin-protease-dependent PFK1 degradation. In addition, study of mechanotransduction utilizing pharmaceutical inhibition indicated that the MFN2 downregulation by 15% stretch was dependent on inactivation of the SP1 (specificity protein 1) and activation of the JNK (c-Jun N-terminal kinase) and ROCK (Rho-associated protein kinase). Adenovirus-mediated MFN2 overexpression or pharmaceutical inhibition of PFK1 suppressed the 15% stretch-induced VSMC proliferation and migration and alleviated neointimal hyperplasia in vein grafts. CONCLUSIONS: MFN2 is a mechanoresponsive protein that interacts with PFK1 to mediate PFK1 degradation and therefore suppresses glycolysis in VSMCs.

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“…It may reflect that activation of lipid metabolismrelated pathways plays a dominant role in tumorigenesis and progression in BC patients with low-risk scores. Finally, there is a bold idea that BC patients in the high-risk group may benefit from therapy targeting glucose MRGs, such as HK3 (37) and PFKP (38). Meanwhile, the novel therapy targeting genes associated with lipid metabolisms, such as HMGCR (39) and FASN (40), may be effective in those at low risk.…”

Section: Metabolic Characteristics Of the Highand Low-risk Groupsmentioning

confidence: 99%

Immunometabolism characteristics and a potential prognostic risk model associated with TP53 mutations in breast cancer

Jiang

Wu²,

Bao³

et al. 2022

Front. Immunol.

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TP53, a gene with high-frequency mutations, plays an important role in breast cancer (BC) development through metabolic regulation, but the relationship between TP53 mutation and metabolism in BC remains to be explored. Our study included 1,066 BC samples from The Cancer Genome Atlas (TCGA) database, 415 BC cases from the Gene Expression Omnibus (GEO) database, and two immunotherapy cohorts. We identified 92 metabolic genes associated with TP53 mutations by differential expression analysis between TP53 mutant and wild-type groups. Univariate Cox analysis was performed to evaluate the prognostic effects of 24 TP53 mutation-related metabolic genes. By unsupervised clustering and other bioinformatics methods, the survival differences and immunometabolism characteristics of the distinct clusters were illustrated. In a training set from TCGA cohort, we employed the least absolute shrinkage and selection operator (LASSO) regression method to construct a metabolic gene prognostic model associated with TP53 mutations, and the GEO cohort served as an external validation set. Based on bioinformatics, the connections between risk score and survival prognosis, tumor microenvironment (TME), immunotherapy response, metabolic activity, clinical characteristics, and gene characteristics were further analyzed. It is imperative to note that our model is a powerful and robust prognosis factor in comparison to other traditional clinical features and also has high accuracy and clinical usefulness validated by receiver operating characteristic (ROC) and decision curve analysis (DCA). Our findings deepen our understanding of the immune and metabolic characteristics underlying the TP53 mutant metabolic gene profile in BC, laying a foundation for the exploration of potential therapies targeting metabolic pathways. In addition, our model has promising predictive value in the prognosis of BC.

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Anti-Warburg effect by targeting HRD1-PFKP pathway may inhibit breast cancer progression

Cited by 13 publications

References 29 publications

VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2

VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2

MFN2 Prevents Neointimal Hyperplasia in Vein Grafts via Destabilizing PFK1

Immunometabolism characteristics and a potential prognostic risk model associated with TP53 mutations in breast cancer

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