Cholesterol Biosynthesis and Homeostasis in Regulation of the Cell Cycle

Singh, Pushpendra; Saxena, Roopali; Srinivas, G.; Pande, Gopal; Chattopadhyay, Amitabha

doi:10.1371/journal.pone.0058833

Cited by 87 publications

(75 citation statements)

References 57 publications

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“…9 These latter functions are implicated in survival signaling pathway activation (eg, Akt) 10 and proliferation. 11,12 For instance, stimulation of cholesterol efflux inhibits interleukin-3 (IL-3)-induced hematological progenitor cell proliferation. 13,14 Interestingly, BPDCN cells express high levels of IL-3 receptor a chain (CD123), and IL-3 is a BPDCN survival factor.…”

Section: Introductionmentioning

confidence: 99%

LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis

Ceroi

Masson

Roggy

et al. 2016

Blood

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Key Points• LXR activation inhibits BPDCN cell survival through the increase of cholesterol efflux, the inhibition of NF-kB, and IL-3 signaling.• Treatment with LXR agonists can be proposed as a new therapeutic approach for BPDCN.Blastic plasmacytoid dendritic cell (PDC) neoplasm (BPDCN) is an aggressive hematological malignancy with a poor prognosis that derives from PDCs. No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared with those of acute myeloid leukemia and T-acute lymphoblastic leukemia, as well as the transcriptomic signature of primary PDCs. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN cells and BPDCN cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation of adenosine triphosphate-binding cassette (ABC) transporters, ABCA1 and ABCG1. LXR agonist treatment was responsible for limiting BPDCN cell proliferation and inducing intrinsic apoptotic cell death. LXR activation in BPDCN cells was shown to interfere with 3 signaling pathways associated with leukemic cell survival, namely: NF-kB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor interleukin-3. These effects were increased by the stimulation of cholesterol efflux through a lipid acceptor, the apolipoprotein A1. In vivo experiments using a mouse model of BPDCN cell xenograft revealed a decrease of leukemic cell infiltration and BPDCN-induced cytopenia associated with increased survival after LXR agonist treatment. This demonstrates that cholesterol homeostasis is modified in BPDCN and can be normalized by treatment with LXR agonists which can be proposed as a new therapeutic approach. (Blood. 2016;128(23):2694-2707

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Section: Introductionmentioning

confidence: 99%

LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis

Ceroi

Masson

Roggy

et al. 2016

Blood

View full text Add to dashboard Cite

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“…17 Moreover, inhibition of cholesterol biosynthesis results in cell cycle arrest in G 0 . 18 In addition, the lipid bilayers of the nuclear envelope and the plasma membrane display different Figure 1. Crosstalk between cell cycle regulators and cellular metabolism.…”

Section: Introductionmentioning

confidence: 99%

Metabolic control of the cell cycle

et al. 2015

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# These authors contributed equally to this work. C ell division is a metabolically demanding process, requiring the production of large amounts of energy and biomass. Not surprisingly therefore, a cell's decision to initiate division is codetermined by its metabolic status and the availability of nutrients. Emerging evidence reveals that metabolism is not only undergoing substantial changes during the cell cycle, but it is becoming equally clear that metabolism regulates cell cycle progression. Here, we overview the emerging role of those metabolic pathways that have been best characterized to change during or influence cell cycle progression. We then studied how Notch signaling, a key angiogenic pathway that inhibits endothelial cell (EC) proliferation, controls EC metabolism (glycolysis) during the cell cycle.

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“…Although discrepancy exists regarding the mechanism of cholesterol-mediated cell cycle arrest, there is agreement that cells fail to enter the S-phase when their cholesterol is depleted. In this respect, cells lacking cholesterol are arrested in either the G 1 (Keyomarsi et al, 1991;Singh et al, 2013), or G 2 phase (Haeffner et al, 1984;Fernandez et al, 2004) until a new source of cholesterol or mevalonate becomes available. Inhibition of the mevalonate pathway could therefore be used to control and synchronize cell cycle directly via the control of cellular cholesterol levels.…”

Section: Cholesterolmentioning

confidence: 99%

Could drugs inhibiting the mevalonate pathway also target cancer stem cells?

Likus

Siemianowicz

Bieńk

et al. 2016

Drug Resistance Updates

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Understanding the connection between metabolic pathways and cancer is very important for the development of new therapeutic approaches based on regulatory enzymes in pathways associated with tumorigenesis. The mevalonate cascade and its rate-liming enzyme HMG CoA-reductase has recently drawn the attention of cancer researchers because strong evidences arising mostly from epidemiologic studies, show that it could promote transformation. Hence, these studies pinpoint HMG CoA-reductase as a candidate proto-oncogene. Several recent epidemiological studies, in different populations, have proven that statins are beneficial for the treatment-outcome of various cancers, and may improve common cancer therapy strategies involving alkylating agents, and antimetabolites. Cancer stem cells/cancer initiating cells (CSC) are key to cancer progression and metastasis. Therefore, in the current review we address the different effects of statins on cancer stem cells. The mevalonate cascade is among the most pleiotropic, and highly interconnected signaling pathways. Through G-protein-coupled receptors (GRCP), it integrates extra-, and intracellular signals. The mevalonate pathway is implicated in cell stemness, cell proliferation, and organ size regulation through the Hippo pathway (e.g. Yap/Taz signaling axis). This pathway is a prime preventive target through the administration of statins for the prophylaxis of obesity-related cardiovascular diseases. Its prominent role in regulation of cell growth and stemness also invokes its role in cancer development and progression. The mevalonate pathway affects cancer metastasis in several ways by: (i) affecting epithelial-to-mesenchymal transition (EMT), (ii) affecting remodeling of Abbreviations: ACAT, acetoacetyl-CoA transferase; acetyl-CoA, acetyl-coenzyme A; Arp2/3, actin-related protein 2/3 (actin polymerizing complex) BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4. 0/). 14 W. Likus et al. / Drug Resistance Updates 25 (2016) 13-25 the cytoskeleton as well as cell motility, (iii) affecting cell polarity (non-canonical Wnt/planar pathway), and (iv) modulation of mesenchymal-to-epithelial transition (MET). Herein we provide an overview of the mevalonate signaling network. We then briefly highlight diverse functions of various elements of this mevalonate pathway. We further discuss in detail the role of elements of the mevalonate cascade in stemness, carcinogenesis, cancer progression, metastasis and maintenance of cancer stem cells.

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Cholesterol Biosynthesis and Homeostasis in Regulation of the Cell Cycle

Cited by 87 publications

References 57 publications

LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis

LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis

Metabolic control of the cell cycle

Could drugs inhibiting the mevalonate pathway also target cancer stem cells?

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