2-Hydroxy-N-arylbenzenesulfonamides as ATP-citrate lyase inhibitors

Li, James J.; Wang, Haixia; Tino, Joseph A.; Robl, Jeffrey A.; Herpin, Timothy F.; Lawrence, R. Michael; Biller, Scott A.; Jamil, Haris; Ponticiello, Randy; Chen, Luping; Chu, Ching-Hsuen; Flynn, Neil; Cheng, Dong; Zhao, Rulin; Chen, Bang‐Chi; Schnur, Dora M.; Obermeier, Mary; Sasseville, Vito G.; Padmanabha, Ramesh; Pike, Kristen; Harrity, Thomas

doi:10.1016/j.bmcl.2007.03.017

Cited by 73 publications

(56 citation statements)

References 15 publications

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Section: Stimulation Of B Lymphocytes With Lps Leads Tosupporting

confidence: 85%

“…C-9 is a cell-permeable 2-hydroxy-N-arylbenzene-sulfonamide analog that specifically inhibits ACLY activity in mammalian cells with an IC 50 ϭ 0.13 M and demonstrates efficacy in vivo mouse models (39). C-9 inhibited endogenous B cell ACLY activity (data not shown), in keeping with previous reports in mammalian cells (39). In control experiments, treatment of splenic B Cells were then collected, cellular lysates were prepared in Triton X-100 buffer, and equivalent amounts of total protein were examined by Western blot for total ACLY (ACLY), ACLY phosphorylated in serine 454 (pACLY-(Ser454)), and ␤-actin as a loading control for electrophoresis, as described previously (6).…”

Section: Stimulation Of B Lymphocytes With Lps Leads Tomentioning

confidence: 99%

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Glucose-dependent de Novo Lipogenesis in B Lymphocytes

Dufort

Gumina

et al. 2014

Journal of Biological Chemistry

142

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Background:The metabolic requirements underlying B lymphocyte differentiation are poorly understood. Results: Differentiation is accompanied by glucose metabolism into fatty acid and cholesterol synthesis, mediated by ATPcitrate lyase (ACLY). Conclusion: ACLY-dependent lipogenesis is required for several phenotypic changes defining plasma cell differentiation. Significance: This study proposes a critical role for ACLY coupled glucose-dependent de novo lipogenesis in LPS-induced B lymphocyte differentiation.

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Section: Stimulation Of B Lymphocytes With Lps Leads Tosupporting

confidence: 85%

Section: Stimulation Of B Lymphocytes With Lps Leads Tomentioning

confidence: 99%

Glucose-dependent de Novo Lipogenesis in B Lymphocytes

Dufort

Gumina

et al. 2014

Journal of Biological Chemistry

142

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“…We reasoned that downregulation of Acly in iBN cells might be involved in cell cycle regulation. To test this idea, BN cells were cultured with the ACL inhibitor BMS303141 (25). Treatment of BN cells with concentrations of BMS303141 above 50 M induced cell cycle arrest (Fig.…”

Section: Resultsmentioning

confidence: 99%

Coordination of Myeloid Differentiation with Reduced Cell Cycle Progression by PU.1 Induction of MicroRNAs Targeting Cell Cycle Regulators and Lipid Anabolism

Solomon

Podder

et al. 2017

Molecular and Cellular Biology

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During macrophage development, myeloid progenitor cells undergo terminal differentiation coordinated with reduced cell cycle progression. Differentiation of macrophages from myeloid progenitors is accompanied by increased expression of the E26 transformation-specific transcription factor PU.1. Reduced PU.1 expression leads to increased proliferation and impaired differentiation of myeloid progenitor cells. It is not understood how PU.1 coordinates macrophage differentiation with reduced cell cycle progression. In this study, we utilized cultured PU.1-inducible myeloid cells to perform genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) analysis coupled with gene expression analysis to determine targets of PU.1 that may be involved in regulating cell cycle progression. We found that genes encoding cell cycle regulators and enzymes involved in lipid anabolism were directly and inducibly bound by PU.1 although their steady-state mRNA transcript levels were reduced. Inhibition of lipid anabolism was sufficient to reduce cell cycle progression in these cells. Induction of PU.1 reduced expression of E2f1, an important activator of genes involved in cell cycle and lipid anabolism, indirectly through microRNA 223. Next-generation sequencing identified microRNAs validated as targeting cell cycle and lipid anabolism for downregulation. These results suggest that PU.1 coordinates cell cycle progression with differentiation through induction of microRNAs targeting cell cycle regulators and lipid anabolism. KEYWORDS E2F1, microRNA, PU.1, cell cycle, differentiation, lipid synthesis, myeloid cells A central problem in biology is understanding how cell division is regulated in response to developmental and environmental cues. During macrophage development, proliferating myeloid progenitor cells undergo terminal differentiation that is coordinated with reduced cell cycle progression (1). However, terminally differentiated macrophages are not necessarily permanently cell cycle arrested, as shown by evidence that epidermal Langerhans cells and brain microglia can reenter the cell cycle to self-renew (2, 3). Thus, cell cycle arrest and terminal differentiation, while normally coincident, can be independently and actively regulated. Much remains to be learned about the mechanisms by which cell-type-specific transcription factors coordinate cell cycle arrest with differentiation.

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“…The reaction was initiated by adding 10 mM ATP at 37°C, and NADH oxidation, as evidenced by a decrease in absorbance at 340 nm, was monitored continuously for 10 min using a microplate reader. To measure the activity of GSK165, a small-molecule inhibitor of ACLy (25) (provided by GlaxoSmithKline, Collegeville, PA, under a material transfer agreement), 400 µg of purified ACLy was used in a final volume of 100 µl. Controls not containing ACLy were used to account for nonspecific NADH oxidation.…”

Section: Methodsmentioning

confidence: 99%

ATP Citrate Lyase Mediates Resistance of Colorectal Cancer Cells to SN38

Zhou

Bollu

Tozzi

et al. 2013

Molecular Cancer Therapeutics

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Combination chemotherapy is standard for metastatic colorectal cancer (CRC); however, nearly all patients develop drug resistance. Understanding the mechanisms that lead to resistance to individual chemotherapeutic agents may enable identification of novel targets and more effective therapy. Irinotecan is commonly used in first- and second-line therapy for patients with metastatic CRC, with the active metabolite being SN38. Emerging evidence suggests that altered metabolism in cancer cells is fundamentally involved in the development of drug resistance. Using Oncomine and unbiased proteomic profiling, we found that ATP citrate lyase (ACLy), the first-step rate-limiting enzyme for de novo lipogenesis, was upregulated in CRC compared to its levels in normal mucosa and in chemoresistant CRC cells compared to isogenic chemo-naïve CRC cells. Overexpression of exogenous ACLy by lentivirus transduction in chemo-naïve CRC cells led to significant chemoresistance to SN38 but not to 5-fluorouracil or oxaliplatin. Knockdown of ACLy by siRNA or inhibition of its activity by a small-molecule inhibitor sensitized chemo-naïve CRC cells to SN38. Furthermore, ACLy was significantly increased in cancer cells that had acquired resistance to SN38. In contrast to chemo-naïve cells, targeting ACLy alone was not effective in re-sensitizing resistant cells to SN38, due to a compensatory activation of the AKT pathway triggered by ACLy suppression. Combined inhibition of AKT signaling and ACLy successfully re-sensitized SN38-resistant cells to SN38. We conclude that targeting ACLy may improve the therapeutic effects of irinotecan and that simultaneous targeting of ACLy and AKT may be warranted to overcome SN38 resistance.

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2-Hydroxy-N-arylbenzenesulfonamides as ATP-citrate lyase inhibitors

Cited by 73 publications

References 15 publications

Glucose-dependent de Novo Lipogenesis in B Lymphocytes

Glucose-dependent de Novo Lipogenesis in B Lymphocytes

Coordination of Myeloid Differentiation with Reduced Cell Cycle Progression by PU.1 Induction of MicroRNAs Targeting Cell Cycle Regulators and Lipid Anabolism

ATP Citrate Lyase Mediates Resistance of Colorectal Cancer Cells to SN38

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