PPARγ is dispensable for clear cell renal cell carcinoma progression

Sanchez, Danielle J.; Steger, David J.; Skuli, Nicolas; Bansal, Ankita; Simon, M. Celeste

doi:10.1016/j.molmet.2018.05.013

Cited by 19 publications

(16 citation statements)

References 45 publications

(52 reference statements)

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“…This example clinically shows the pro-anakoinotic synergy effects of transcriptional modulators. Induction of continuous complete remission with dual transcriptional modulation only, supports current experimental data, showing that PPARγ plays neither a tumor-suppressive nor an oncogenic role in advanced renal clear cell carcinoma, and that single-agent PPARγ agonists are unlikely to be effective for the treatment of this disease (Sanchez et al, 2018 ).…”

Section: Master Modulators the Backbone Of Anakoinosis Inducing Thersupporting

confidence: 65%

Clinical Efficacy of a Novel Therapeutic Principle, Anakoinosis

et al. 2018

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Classic tumor therapy, consisting of cytotoxic agents and/or targeted therapy, has not overcome therapeutic limitations like poor risk genetic parameters, genetic heterogeneity at different metastatic sites or the problem of undruggable targets. Here we summarize data and trials principally following a completely different treatment concept tackling systems biologic processes: the principle of communicative reprogramming of tumor tissues, i.e., anakoinosis (ancient greek for communication), aims at establishing novel communicative behavior of tumor tissue, the hosting organ and organism via re-modeling gene expression, thus recovering differentiation, and apoptosis competence leading to cancer control – in contrast to an immediate, “poisoning” with maximal tolerable doses of targeted or cytotoxic therapies. Therefore, we introduce the term “Master modulators” for drugs or drug combinations promoting evolutionary processes or regulating homeostatic pathways. These “master modulators” comprise a broad diversity of drugs, characterized by the capacity for reprogramming tumor tissues, i.e., transcriptional modulators, metronomic low-dose chemotherapy, epigenetically modifying agents, protein binding pro-anakoinotic drugs, such as COX-2 inhibitors, IMiDs etc., or for example differentiation inducing therapies. Data on 97 anakoinosis inducing schedules indicate a favorable toxicity profile: The combined administration of master modulators, frequently (with poor or no monoactivity) may even induce continuous complete remission in refractory metastatic neoplasia, irrespectively of the tumor type. That means recessive components of the tumor, successively developing during tumor ontogenesis, are accessible by regulatory active drug combinations in a therapeutically meaningful way. Drug selection is now dependent on situative systems characteristics, to less extent histology dependent. To sum up, anakoinosis represents a new substantive therapy principle besides novel targeted therapies.

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Section: Master Modulators the Backbone Of Anakoinosis Inducing Thersupporting

confidence: 65%

Clinical Efficacy of a Novel Therapeutic Principle, Anakoinosis

et al. 2018

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“…In the PPAR␥ cistrome of adipocytes, these two TFs show the highest motif enrichment. In contrast to previous results and assumptions drawn based on reporter assays and high-throughput DNA-protein interaction assays, a conserved, up to 4-nucleotidelong 5= extension of PPAR␥ binding sites could be observed in both human and mouse cells by using ChIP-seq-based motif enrichment analyses (18)(19)(20). However, the approaches resulting in position weight matrices (PWMs) of the motifs also have major technical limitations.…”

mentioning

confidence: 83%

Unraveling the Hierarchy of cis and trans Factors That Determine the DNA Binding by Peroxisome Proliferator-Activated Receptor γ

Nagy

Dániel

Cuaranta-Monroy

et al. 2020

Molecular and Cellular Biology

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Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor essential for adipocyte development and the maintenance of the alternatively polarized macrophage phenotype. Biochemical studies have established that as an obligate heterodimer with retinoid X receptor (RXR), PPARγ binds directly repeated nuclear receptor half sites spaced by one nucleotide (direct repeat 1 [DR1]). However, it has not been analyzed systematically and genome-wide how cis factors such as the sequences of DR1s and adjacent sequences and trans factors such as cobinding lineage-determining transcription factors (LDTFs) contribute to the direct binding of PPARγ in different cellular contexts. We developed a novel motif optimization approach using sequence composition and chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) densities from macrophages and adipocytes to complement de novo motif enrichment analysis and to define and classify high-affinity binding sites. We found that approximately half of the PPARγ cistrome represents direct DNA binding; both half sites can be extended upstream, and these are typically not of equal strength within a DR1. Strategically positioned LDTFs have greater impact on PPARγ binding than the quality of DR1, and the presence of the extension of DR1 provides a remarkable synergy with LDTFs. This approach of considering not only nucleotide frequencies but also their contribution to protein binding in a cellular context is applicable to other transcription factors.

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“…More than 90% of ccRCC tumors show constitutive activation of the hypoxia-inducible factor (HIF) proteins due to biallelic inactivation of the tumor suppressor von Hippel-Lindau (VHL) gene (4). Histologically, ccRCC is characterized by the "clear-cell" phenotype resulting from lipid and glycogen accumulation, suggesting that altered fatty acid and glucose metabolism play a crucial role in the development of this cancer (5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Gamma-Glutamyltransferase 1 Promotes Clear Cell Renal Cell Carcinoma Initiation and Progression

Bansal

Sanchez

Nimgaonkar

et al. 2019

Molecular Cancer Research

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Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer. While the localized form of this disease can be treated surgically, advanced and metastatic stages are resistant to chemotherapies. Although more innovative treatments, such as targeted or immune-based therapies, exist, the need for new therapeutic options remains. ccRCC presents unique metabolic signatures and multiple studies have reported a significant increase in levels of reduced glutathione (GSH) and its precursors in ccRCC tumor samples compared with normal kidney tissues. These observations led us to investigate the effects of blocking the GSH pathway, particularly the gamma-glutamyltransferase 1 (GGT1) enzyme, in multiple ccRCC cell lines. In this study, we provide in vitro and in vivo evidence that GGT1/GSH pathway inhibition impacts ccRCC cell growth, through increased cell-cycle arrest. Of note, GGT1 inhibition also impairs ccRCC cell migration. Finally, pharmacologic GSH pathway inhibition decreases ccRCC cell proliferation and increases sensitivity to standard chemotherapy. Our results suggest that GGT1/GSH pathway inhibition represents a new strategy to overcome ccRCC chemoresistance. Implications: GGT1/GSH pathway inhibition represents a promising therapeutic strategy to overcome chemoresistance and inhibit progression of ccRCC tumors.

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PPARγ is dispensable for clear cell renal cell carcinoma progression

Cited by 19 publications

References 45 publications

Clinical Efficacy of a Novel Therapeutic Principle, Anakoinosis

Clinical Efficacy of a Novel Therapeutic Principle, Anakoinosis

Unraveling the Hierarchy of cis and trans Factors That Determine the DNA Binding by Peroxisome Proliferator-Activated Receptor γ

Gamma-Glutamyltransferase 1 Promotes Clear Cell Renal Cell Carcinoma Initiation and Progression

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