HRD1 attenuates the high uptake of [18F]FDG in hepatocellular carcinoma PET imaging

Li, Aimei; Lin, Xia-Wen; Shen, Jingtao; Li, Min; Zheng, Qi‐Huang; Zhou, Zhengyang; Shi, Ming

doi:10.1016/j.nucmedbio.2021.02.006

Cited by 6 publications

(4 citation statements)

References 24 publications

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“…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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“…Increasing evidence have indicated that the GLUT1 could function as a positive regulator of HCC's proliferation or metastasis (90)(91)(92)(93). Li et al, 2021 indicated that the HCC has the high uptake of [( 18)F]FDG feature and Xia et al, 2020 revealed that the glucose transporter represented by GLUT1 impacted (18)F-fluorodeoxyglucose PET-CT imaging in hepatocellular carcinoma (94,95). Results from Yi et al, 2020 showed that repressing of GLUT1 via miR-328-3p not only exert antiproliferative activation but also enhanced the sensitivity of cells to chemotherapeutics (96).…”

Section: Discussionmentioning

confidence: 99%

A Novel Microcrystalline BAY-876 Formulation Achieves Long-Acting Antitumor Activity Against Aerobic Glycolysis and Proliferation of Hepatocellular Carcinoma

et al. 2021

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BAY-876 is an effective antagonist of the Glucose transporter type 1 (GLUT1) receptor, a mediator of aerobic glycolysis, a biological process considered a hallmark of hepatocellular carcinoma (HCC) together with cell proliferation, drug-resistance, and metastasis. However, the clinical application of BAY-876 has faced many challenges. In the presence study, we describe the formulation of a novel microcrystalline BAY-876 formulation. A series of HCC tumor models were established to determine not only the sustained release of microcrystalline BAY-876, but also its long-acting antitumor activity. The clinical role of BAY-876 was confirmed by the increased expression of GLUT1, which was associated with the worse prognosis among advanced HCC patients. A single dose of injection of microcrystalline BAY-876 directly in the HCC tissue achieved sustained localized levels of Bay-876. Moreover, the single injection of microcrystalline BAY-876 in HCC tissues not only inhibited glucose uptake and prolonged proliferation of HCC cells, but also inhibited the expression of epithelial-mesenchymal transition (EMT)-related factors. Thus, the microcrystalline BAY-876 described in this study can directly achieve promising localized effects, given its limited diffusion to other tissues, thereby reducing the occurrence of potential side effects, and providing an additional option for advanced HCC treatment.

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“…Additionally, 6 weeks after liver‐specific deletion of HRD1 in mice, growth retardation was observed in these mice compared with that in their wild type littermates 129 . Furthermore, HRD1 dysregulation in expression was linked with several cancer subtypes including colon cancer, 179 breast cancer, 180,181 and hepatocellular carcinoma 182 …”

Section: Human Phenotypes and Animal And Cellular Disease Models Asso...mentioning

confidence: 99%

“…129 Furthermore, HRD1 dysregulation in expression was linked with several cancer subtypes including colon cancer, 179 breast cancer, 180,181 and hepatocellular carcinoma. 182 Another prominent E3 ligase is the ER membrane-bound glycoprotein gp78, also known as autocrine motility factor receptor (AMFR).…”

Section: Erlin1mentioning

confidence: 99%

Genetic disruption of mammalian endoplasmic reticulum‐associated protein degradation: Human phenotypes and animal and cellular disease models

Badawi

Mohamed

Varghese

et al. 2023

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Endoplasmic reticulum-associated protein degradation (ERAD) is a stringent quality control mechanism through which misfolded, unassembled and some native proteins are targeted for degradation to maintain appropriate cellular and organelle homeostasis. Several in vitro and in vivo ERAD-related studies have provided mechanistic insights into ERAD pathway activation and its consequent events; however, a majority of these have investigated the effect of ERAD substrates and their consequent diseases affecting the degradation process. In this review, we present all reported human single-gene disorders caused by genetic variation in genes that encode ERAD components rather than their substrates. Additionally, after extensive literature survey, we present various genetically manipulated higher cellular and mammalian animal models that lack specific components involved in various stages of the ERAD pathway.

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HRD1 attenuates the high uptake of [18F]FDG in hepatocellular carcinoma PET imaging

Cited by 6 publications

References 24 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

A Novel Microcrystalline BAY-876 Formulation Achieves Long-Acting Antitumor Activity Against Aerobic Glycolysis and Proliferation of Hepatocellular Carcinoma

Genetic disruption of mammalian endoplasmic reticulum‐associated protein degradation: Human phenotypes and animal and cellular disease models

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