Lipid Regulatory Proteins as Potential Therapeutic Targets for Ovarian Cancer in Obese Women

Yang, Jing; Stack, M. Sharon

doi:10.3390/cancers12113469

Cited by 25 publications

(27 citation statements)

References 226 publications

(393 reference statements)

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“…A decrease in CYP3A4 induction by rifampicin in the presence of SREBP1 was also observed [102]. Considering that expression of SREBP1 is altered in cancer [153] and metabolic disorders [154], changes in PXR activity under these conditions may also be expected.…”

Section: Other Corepressorsmentioning

confidence: 86%

Regulation of PXR Function by Coactivator and Corepressor Proteins: Ligand Binding Is Just the Beginning

Rigalli

Theile

Nilles

et al. 2021

Cells

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The pregnane X receptor (PXR, NR1I2) is a nuclear receptor which exerts its regulatory function by heterodimerization with the retinoid-X-receptor α (RXRα, NR2B1) and binding to the promoter and enhancer regions of diverse target genes. PXR is involved in the regulation of drug metabolism and excretion, metabolic and immunological functions and cancer pathogenesis. PXR activity is strongly regulated by the association with coactivator and corepressor proteins. Coactivator proteins exhibit histone acetyltransferase or histone methyltransferase activity or associate with proteins having one of these activities, thus promoting chromatin decondensation and activation of the gene expression. On the contrary, corepressor proteins promote histone deacetylation and therefore favor chromatin condensation and repression of the gene expression. Several studies pointed to clear cell- and ligand-specific differences in the activation of PXR. In this article, we will review the critical role of coactivator and corepressor proteins as molecular determinants of the specificity of PXR-mediated effects. As already known for other nuclear receptors, understanding the complex mechanism of PXR activation in each cell type and under particular physiological and pathophysiological conditions may lead to the development of selective modulators with therapeutic potential.

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Section: Other Corepressorsmentioning

confidence: 86%

Regulation of PXR Function by Coactivator and Corepressor Proteins: Ligand Binding Is Just the Beginning

Rigalli

Theile

Nilles

et al. 2021

Cells

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“…As obesity increases the risk of OC progression and leads to enhanced tumor burden [ 38 ], HFD-induced obesity resulted in a shorter survival regardless of the CXCR2 in adipose tissues ( Figure 2 B). A shorter survival may be due to a greater tumor and ascites burden in the HFD-fed CXCR2 WT and cKO, respectively ( Figure 2 D,F).…”

Section: Discussionmentioning

confidence: 99%

High-Fat Diet-Induced Obese Effects of Adipocyte-Specific CXCR2 Conditional Knockout in the Peritoneal Tumor Microenvironment of Ovarian Cancer

Choe

Lee

Beeghly–Fadiel

et al. 2021

Cancers

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Obesity contributes to ovarian cancer (OC) progression via tumorigenic chemokines. Adipocytes and OC cells highly express CXCR2, and its ligands CXCL1/8, respectively, indicating that the CXCL1/8-CXCR2 axis is a molecular link between obesity and OC. Here, we investigated how the adipocyte-specific CXCR2 conditional knockout (cKO) affected the peritoneal tumor microenvironment of OC in a high-fat diet (HFD)-induced obese mouse model. We first generated adipocyte-specific CXCR2 cKO in mice: adipose tissues were not different in crown-like structures and adipocyte size between the wild-type (WT) and cKO mice but expressed lower levels of CCL2/6 compared to the obese WT mice. HFD-induced obese mice had a shorter survival time than lean mice. Particularly, obese WT and cKO mice developed higher tumors and ascites burdens, respectively. The ascites from the obese cKO mice showed increased vacuole clumps but decreased the floating tumor burden, tumor-attached macrophages, triglyceride, free fatty acid, CCL2, and TNF levels compared to obese WT mice. A tumor analysis revealed that obese cKO mice attenuated inflammatory areas, PCNA, and F4/80 compared to obese WT mice, indicating a reduced tumor burden, and there were positive relationships between the ascites and tumor parameters. Taken together, the adipocyte-specific CXCR2 cKO was associated with obesity-induced ascites despite a reduced tumor burden, likely altering the peritoneal tumor microenvironment of OC.

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“…Several small-molecule inhibitors of SREBPs are available, such as fatostatin, botulin, and PF-429242. These inhibitors have demonstrated anti-tumor effects in various cancers in preclinical studies [ 130 ]. Importantly, SREBP-1 inhibition can sensitize resistant mutant BRAF melanoma both in vitro and in vivo models [ 146 ].…”

Section: Targeting Phenotypic Plasticity: Identifying New Vulnerabili...mentioning

confidence: 99%

Understanding Molecular Mechanisms of Phenotype Switching and Crosstalk with TME to Reveal New Vulnerabilities of Melanoma

Najem

Soumoy

Sabbah

et al. 2022

Cells

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Melanoma cells are notorious for their high plasticity and ability to switch back and forth between various melanoma cell states, enabling the adaptation to sub-optimal conditions and therapeutics. This phenotypic plasticity, which has gained more attention in cancer research, is proposed as a new paradigm for melanoma progression. In this review, we provide a detailed and deep comprehensive recapitulation of the complex spectrum of phenotype switching in melanoma, the key regulator factors, the various and new melanoma states, and corresponding signatures. We also present an extensive description of the role of epigenetic modifications (chromatin remodeling, methylation, and activities of long non-coding RNAs/miRNAs) and metabolic rewiring in the dynamic switch. Furthermore, we elucidate the main role of the crosstalk between the tumor microenvironment (TME) and oxidative stress in the regulation of the phenotype switching. Finally, we discuss in detail several rational therapeutic approaches, such as exploiting phenotype-specific and metabolic vulnerabilities and targeting components and signals of the TME, to improve the response of melanoma patients to treatments.

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Lipid Regulatory Proteins as Potential Therapeutic Targets for Ovarian Cancer in Obese Women

Cited by 25 publications

References 226 publications

Regulation of PXR Function by Coactivator and Corepressor Proteins: Ligand Binding Is Just the Beginning

Regulation of PXR Function by Coactivator and Corepressor Proteins: Ligand Binding Is Just the Beginning

High-Fat Diet-Induced Obese Effects of Adipocyte-Specific CXCR2 Conditional Knockout in the Peritoneal Tumor Microenvironment of Ovarian Cancer

Understanding Molecular Mechanisms of Phenotype Switching and Crosstalk with TME to Reveal New Vulnerabilities of Melanoma

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