Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis

Flaveny, Colin A.; Griffett, Kristine; El-Gendy, Bahaa El Dien M.; Kazantzis, Melissa; Sengupta, Monideepa; Amelio, Antonio L.; Chatterjee, Arindam; Walker, John K.; Solt, Laura A.; Kamenecka, Theodore M.; Burris, Thomas P.

doi:10.1016/j.ccell.2015.05.007

Cited by 167 publications

(173 citation statements)

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“…Although RXR-specific inverse agonists are not yet available, similar compounds have already been developed and used successfully in preclinical studies for several other nuclear receptors including RAR, LXR, and ROR (30)(31)(32)(33). This class of RXR-specific ligands could enhance the repressive effect of RXR on prometastatic regulators, potentially rendering the lung microenvironment less permissive toward metastatic colonization.…”

Section: Discussionmentioning

confidence: 99%

Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism

Kiss

Czimmerer

Nagy

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Retinoid X receptor (RXR) regulates several key functions in myeloid cells, including inflammatory responses, phagocytosis, chemokine secretion, and proangiogenic activity. Its importance, however, in tumor-associated myeloid cells is unknown. In this study, we demonstrate that deletion of RXR in myeloid cells enhances lung metastasis formation while not affecting primary tumor growth. We show that RXR deficiency leads to transcriptomic changes in the lung myeloid compartment characterized by increased expression of prometastatic genes, including important determinants of premetastatic niche formation. Accordingly, RXR-deficient myeloid cells are more efficient in promoting cancer cell migration and invasion. Our results suggest that the repressive activity of RXR on prometastatic genes is mediated primarily through direct DNA binding of the receptor along with nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressors and is largely unresponsive to ligand activation. In addition, we found that expression and transcriptional activity of RXRα is down-modulated in peripheral blood mononuclear cells of patients with lung cancer, particularly in advanced and metastatic disease. Overall, our results identify RXR as a regulator in the myeloid cell-assisted metastatic process and establish lipid-sensing nuclear receptors in the microenvironmental regulation of tumor progression.is a member of the nuclear receptor superfamily of ligand-dependent transcription factors that bind various lipophilic hormones and lipid metabolites. Sensing the lipid milieu by RXR, in concert with other nuclear receptors, plays critical roles in physiology, including the regulation of organogenesis, lipid metabolism, and skin homeostasis (1). RXR is able to bind vitamin A derivatives 9-cis-retinoic acid and 9-cis-13,14-dihydroretinoic acid as well as fatty acids such as docosahexanoic acid and phytanic acid (1, 2). The receptor has three isotypes, RXRα, RXRβ, and RXRγ, which appear to be functionally interchangeable in tissues in which more than one isotype is expressed (3). RXR has a unique integrative function in nuclear receptor signaling because of its ability to form homodimers as well as heterodimers with several other members of the superfamily, such as PPAR, LXR, RAR, and VDR. RXR and its heterodimers have a profound effect on the function of myeloid cells by linking cellular metabolism and immune function (4, 5). Specific activation of RXR has been shown to up-regulate chemokine expression, promote phagocytosis of apoptotic cells, and attenuate antiviral responses in myeloid cells (6-8). To further delineate the function of the receptor, we recently mapped the genomic binding sites of RXR in macrophages and identified a network of RXR-bound enhancers that control angiogenic genes including Vegfa, Hbegf, Litaf, and Hipk2 (9). Activation of these enhancers by RXR induced a proangiogenic transcriptional program and phenotype (9). Interestingly, we found that half of the 5...

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Section: Discussionmentioning

confidence: 99%

Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism

Kiss

Czimmerer

Nagy

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Synthetic LXR ligands include the pan-LXR activating compounds GW3965 and T0901217, and the intestinal tissue-specific ligand GW6340 [48]. Conversely, inverse agonists such as the recently described SR9243 inhibit LXR-mediated gene expression [37]. Such inverse agonists reduce receptor function by inducing co-repressor interaction.…”

Section: Cholesterol Metabolismmentioning

confidence: 99%

The Contribution of Cholesterol and Its Metabolites to the Pathophysiology of Breast Cancer

Baek

Nelson

2016

HORM CANC

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As the most common cancer in women, one in eight will develop invasive breast cancer over their lifetime making it the second most common cause of cancer-related death among women. Of the many known risk factors for developing breast cancer, obesity stands out as prominent and modifiable. Interestingly, elevated cholesterol is highly associated with obesity, and has emerged as an independent risk factor for breast cancer onset and recurrence. This indicates that cholesterol also contributes to the breast cancer-pathogenicity of obesity. This review highlights our current understanding of the mechanisms by which cholesterol impacts breast cancer. Key preclinical studies have been highlighted, including discussion of homeostatic control of cholesterol levels, signaling by cholesterol metabolites through the estrogen receptors, cholesterol formation of lipid rafts and subsequent signaling, and the potential roles of cholesterol in creating a pro-inflammatory tumor microenvironment. Future directions and avenues for therapeutic exploitation are also considered.

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“…Flaveny et al (2015) show that SR9243 specifically induces expression of TNF-a in tumor cells and suggest that SR9243 could ''unmask'' tumors to be recognized by the immune system. Cytokines in the tumor microenvironment are acknowledged as important factors involved in the control of tumor growth.…”

mentioning

confidence: 91%

“…In this issue of Cancer Cell, Flaveny et al (2015) target LXR by designing and synthesizing an inverse agonist (SR9243). They show that both the Warbug effect and lipogenesis are inhibited in cancer cells upon treatment with SR9243, and this consequently leads to apoptosis of cancer cells.…”

mentioning

confidence: 99%

“…While the anti-inflammatory role of LXR is well documented, the cross talk between the effect of LXR signaling in metabolism and the LXR-mediated modulation of the immune response dealing with tumors has only recently been investigated. While Flaveny et al (2015) provide interesting evidence that targeting LXRs to suppress glycolysis and lipogenesis is a promising new strategy for cancer treatment, further studies investigating the impact and association of LXR signaling in metabolism, immunity/inflammation, and proliferation might unravel novel mechanisms to advance the battle against cancer. And the inverse agonist SR9243 could prove a valuable tool in this quest.…”

mentioning

confidence: 99%

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Are Synthetic Compounds that Silence the Liver-X-Receptor the Next Generation of Anti-cancer Drugs?

Steffensen

2015

Cancer Cell

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Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis

Cited by 167 publications

References 50 publications

Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism

Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism

The Contribution of Cholesterol and Its Metabolites to the Pathophysiology of Breast Cancer

Are Synthetic Compounds that Silence the Liver-X-Receptor the Next Generation of Anti-cancer Drugs?

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