PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia

Tung, Stephanie; Shi, Yonghong; Wong, Karry; Zhu, Fang; Gorczynski, Reg; Laister, Robert C.; Minden, Mark D.; Blechert, Anne-Kareen; Genzel, Yvonne; Reichl, Udo; Spaner, David

doi:10.1182/blood-2013-03-489468

Cited by 85 publications

(81 citation statements)

References 40 publications

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“…PPARα was previously shown to mediate protection of CLL cells from harsh microenvironmental conditions, including the presence of cytotoxic agents (23,30). This result suggests that PPARα plays a role in CLL cell viability.…”

Section: Pparα Antagonist Is Cytotoxic To Cll Cells Even In the Presesupporting

confidence: 60%

“…PPARα is overexpressed in CLL cells and helps to protect them from harsh microenvironmental conditions. MK886, a small molecule that is reported to have PPARα antagonist properties, exhibits anti-CLL activity in vitro and in vivo (23,30 (Figures 2, 3), but was less cytotoxic to B cells isolated from healthy volunteers ( Supplementary Figure S1). Because accessory cells can rescue CLL cells from spontaneous and drug-induced apoptosis (43)(44)(45), as well as protect CLL cells from fludarabineinduced apoptosis in vitro (31), it is essential to evaluate potential therapeutics in CLL accessory cell cocultures.…”

Section: Discussionmentioning

confidence: 99%

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A Selective Novel Peroxisome Proliferator-Activated Receptor (PPAR)-α Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo

Messmer

Lorrain

Stebbins

et al. 2015

Mol Med

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Tumor-specific metabolic changes can reveal new therapeutic targets. Our findings implicate a supporting role for fatty acid metabolism in chronic lymphocytic leukemia (CLL) cell survival. Peroxisome proliferator-activated receptor (PPAR)-α, a major transcriptional regulator of fatty acid oxidation, was recently shown to be upregulated in CLL. To evaluate PPARα as a potential therapeutic target, we developed a highly selective, potent small molecule antagonist of PPARα, NXT629. NXT629 inhibited agonistinduced transcription of PPARα-regulated genes, demonstrating target engagement in CLL cells. Furthermore, NXT629 induced apoptosis of CLL cells even in the presence of a protective microenvironment. To mimic the proliferative lymphoid compartment of CLL, we examined the activity of NXT629 on CLL cells that were stimulated to proliferate in vitro. NXT629 reduced the number of leukemia cells undergoing cell division. In addition, in two xenograft mouse models of CLL (one a model for nondividing and one for dividing CLL), NXT629 reduced the number of viable CLL cells in vivo. Overall, these results suggest that fatty acid metabolism promotes survival and proliferation of primary CLL cells and that inhibiting PPARα gene regulation could be a new therapeutic approach to treating CLL.

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Section: Pparα Antagonist Is Cytotoxic To Cll Cells Even In the Presesupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

A Selective Novel Peroxisome Proliferator-Activated Receptor (PPAR)-α Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo

Messmer

Lorrain

Stebbins

et al. 2015

Mol Med

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“…Some kinases or their activators can also lead to specific inhibition of PPAR transcriptional activity, such as the MEK1 or AMP-activated protein kinase activators 5-aminoimidazole-4-carboxamide riboside [26,27]. Furthermore, it was shown very recently that PPAR inhibition could improve the therapeutic efficacy of glucocorticoids in aggressive forms of chronic lymphocytic leukemia [28]. Thus, PPAR inhibition could be used in V9V2 T cell-based cancer immunotherapy.…”

Section: Resultsmentioning

confidence: 99%

The PPARα pathway in Vγ9Vδ2 T cell anergy

Poupot

Boissard

Bétous

et al. 2014

Cellular and Molecular Biology Letters

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Phosphoantigens (PAgs) activate V9V2 T lymphocytes, inducing their potent and rapid response in vitro and in vivo. However, humans and nonhuman primates that receive repeated injections of PAgs progressively lose their V9V2 T cell response to them. To elucidate the molecular mechanisms of this in vivo desensitization, we analyzed the transcriptome of circulating V9V2 T cells from macaques injected with PAg. We showed that three PAg injections induced the activation of the PPAR pathway in V9V2 T cells. Thus, we analyzed the in vitro response of V9V2 T cells stimulated with a PPAR agonist. We demonstrated that in vitro PPAR pathway activation led to the inhibition of the BrHPP-induced activation and proliferation of human V9V2 T cells. Since the PPAR pathway is involved in the antigen-selective desensitization of human V9V2 T cells, the use of PPAR inhibitors could enhance cancer immunotherapy based on V9V2 T cells.

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“…Quantification of specific RNA transcripts was performed as before 20 with the primers listed in supplemental Figure 9.…”

Section: Quantitative Reverse Transcription-polymerase Chain Reactionmentioning

confidence: 99%

Microenvironmental interleukin-6 suppresses toll-like receptor signaling in human leukemia cells through miR-17/19A

Shi

McCaw

et al. 2015

Blood

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Key Points• IL-6 from splenic stromal cells prevents CLL cells from responding strongly to TLR ligands.• IL-6-signaling inhibitors enhance TLR-mediated responses of CLL cells in vitro and in vivo.The regulation of toll-like receptor (TLR) signaling in a tumor microenvironment is poorly understood despite its importance in cancer biology. To address this problem, TLR7-responses of chronic lymphocytic leukemia (CLL) cells were studied in the presence and absence of a human stromal cell-line derived from a leukemic spleen. CLL cells alone produced high levels of tumor necrosis factor (TNF)-a and proliferated in response to TLR7-agonists. A signal transducer and activator of transcription 3 -activating stromal factor, identified as interleukin (IL)-6, was found to upregulate microRNA (miR)-17 and miR-19a, target TLR7 and TNFA messenger RNA, and induce a state of tolerance to TLR7-agonists in CLL cells. Overexpression of the miR-17-92 cluster tolerized CLL cells directly and miR-17 and miR-19a antagomiRs restored TLR7-signaling. Inhibition of IL-6 signaling with antibodies or small-molecule Janus kinase inhibitors reversed tolerization and increased TLR7-stimulated CLL cell numbers in vitro and in NOD-SCIDg c null mice. These results suggest IL-6 can act as tumor suppressor in CLL by inhibiting TLR-signaling. (Blood. 2015;126(6):766-778)

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PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia

Cited by 85 publications

References 40 publications

A Selective Novel Peroxisome Proliferator-Activated Receptor (PPAR)-α Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo

A Selective Novel Peroxisome Proliferator-Activated Receptor (PPAR)-α Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo

The PPARα pathway in Vγ9Vδ2 T cell anergy

Microenvironmental interleukin-6 suppresses toll-like receptor signaling in human leukemia cells through miR-17/19A

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