scholarly journals Intracellular Role for Sphingosine Kinase 1 in Intestinal Adenoma Cell Proliferation

2006 ◽  
Vol 26 (19) ◽  
pp. 7211-7223 ◽  
Author(s):  
Masataka Kohno ◽  
Michiko Momoi ◽  
Myat Lin Oo ◽  
Ji-Hye Paik ◽  
Yong-Moon Lee ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Epithelial Cell ◽  
Tumor Cell ◽  
Sphingosine Kinase ◽  
Sphingolipid Metabolism ◽  
Intestinal Tumor ◽  
Epithelial Cell Proliferation ◽  
Tumor Cell Proliferation ◽  
Adenoma Cell

ABSTRACT Sphingosine kinase (Sphk) enzymes are important in intracellular sphingolipid metabolism as well as in the biosynthesis of sphingosine 1-phosphate (S1P), an extracellular lipid mediator. Here, we show that Sphk1 is expressed and is required for small intestinal tumor cell proliferation in Apc Min/+ mice. Adenoma size but not incidence was dramatically reduced in Apc Min/+ Sphk −/ − mice. Concomitantly, epithelial cell proliferation in the polyps was significantly attenuated, suggesting that Sphk1 regulates adenoma progression. Although the S1P receptors (S1P1R, S1P2R, and S1P3R) are expressed, polyp incidence or size was unaltered in Apc Min/+ S1p2r −/ −, Apc Min/+ S1p3r −/ −, and Apc Min/+ S1p1r +/ − bigenic mice. These data suggest that extracellular S1P signaling via its receptors is not involved in adenoma cell proliferation. Interestingly, tissue sphingosine content was elevated in the adenomas of Apc Min/ + Sphk1 −/ − mice, whereas S1P levels were not significantly altered. Concomitantly, epithelial cell proliferation and the expression of the G1/S cell cycle regulator CDK4 and c-myc were diminished in the polyps of Apc Min/ + Sphk1 −/ − mice. In rat intestinal epithelial (RIE) cells in vitro, Sphk1 overexpression enhanced cell cycle traverse at the G1/S boundary. In addition, RIE cells treated with sphingosine but not C6-ceramide exhibited reduced cell proliferation, reduced retinoblastoma protein phosphorylation, and cyclin-dependent kinase 4 (Cdk4) expression. Our findings suggest that Sphk1 plays a critical role in intestinal tumor cell proliferation and that inhibitors of Sphk1 may be useful in the control of intestinal cancer.

scholarly journals Effects of 4E-BP1 expression on hypoxic cell cycle inhibition and tumor cell proliferation and survival

2008 ◽  
Vol 7 (9) ◽  
pp. 1441-1449 ◽  
Author(s):  
Bryan C. Barnhart ◽  
Jennifer C. Lam ◽  
Regina M. Young ◽  
Peter J. Houghton ◽  
Brian Keith ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Cell ◽  
Hypoxic Cell ◽  
Tumor Cell Proliferation ◽  
Cell Cycle Inhibition

scholarly journals Progesterone Inhibits the Estrogen-Induced Phosphoinositide 3-Kinase→AKT→GSK-3β→Cyclin D1→pRB Pathway to Block Uterine Epithelial Cell Proliferation

2005 ◽  
Vol 19 (8) ◽  
pp. 1978-1990 ◽  
Author(s):  
Bo Chen ◽  
Haiyan Pan ◽  
Liyin Zhu ◽  
Yan Deng ◽  
Jeffrey W. Pollard
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Epithelial Cell ◽  
Cyclin D1 ◽  
Nuclear Accumulation ◽  
Nuclear Antigen ◽  
Epithelial Cell Proliferation ◽  
Uterine Epithelial Cell ◽  
Gsk 3Β ◽  
Phosphoinositide 3 Kinase

Abstract The mammalian cell cycle is regulated by the cyclin/cyclin-dependent kinase (CDK) phosphorylation of the retinoblastoma (pRB) family of proteins. Cyclin D1 with its CDK4/6 partners initiates the cell cycle and acts as the link between extracellular signals and the cell cycle machinery. Estradiol-17β (E2) stimulates uterine epithelial cell proliferation, a process that is completely inhibited by pretreatment with progesterone (P4). Previously, we identified cyclin D1 localization as a key point of regulation in these cells with E2 causing its nuclear accumulation and P4 retaining it in the cytoplasm with the resultant inhibition of pRB phosphorylation. Here we show that E2 stimulates phosphoinositide 3-kinase to activate phosphokinase B/AKT to effect an inhibitory phosphorylation of glycogen synthase kinase (GSK-3β). This pathway is suppressed by P4. Inhibition of the GSK-3β activity in P4-treated uteri by the specific inhibitor, LiCl, reversed the nuclear accumulation of cyclin D1 and in doing so, caused pRB phosphorylation and the induction of downstream genes, proliferating cell nuclear antigen and Ki67. Conversely, inhibition of phosphoinositide 3 kinase by LY294002 or Wortmanin reversed the E2-induced GSK-3β Ser9 inhibitory phosphorylation and blocked nuclear accumulation of cyclin D1. These data show the reciprocal actions of E2 and P4 on the phosphoinositide 3-kinase through to the GSK-3β pathway that in turn regulates cyclin D1 localization and cell cycle progression. These data reveal a novel signaling pathway that links E2 and P4 action to growth factor-mediated signaling in the uterus.

scholarly journals Yap Promotes Epithelial Cell Proliferation and Epithelium-derived Innate Cytokine Expression via the NF-κb Pathway in Chronic Rhinosinusitis With Nasal Polyps

2020 ◽  
Author(s):  
Huiyi Deng ◽  
Meijiao Li ◽  
Rui. Zheng ◽  
Huijun Qiu ◽  
Tian Yuan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Epithelial Cell ◽  
Chronic Rhinosinusitis ◽  
Nasal Polyps ◽  
Hippo Pathway ◽  
Signalling Pathway ◽  
Epithelial Cell Proliferation ◽  
Ki 67 ◽  
Pathway Activity

Abstract Objectives: The hippo-yes-associated protein (YAP) pathway plays an important role in epithelial cell proliferation and inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP). However, the underlying mechanisms remain unclear. This study intends to investigate the role of YAP and the nuclear factor kappa-B (NF-κB) signalling pathway in nasal epithelial cell proliferation and the expression of epithelium-derived cytokines in CRSwNP.Methods: The expression levels of YAP, TEAD1, Ki-67, and NF-κB in sinonasal mucosa, primary nasal epithelial cells (NPECs), and human nasal epithelial RPMI 2650 cells were detected by RT-qPCR and immunoblotting. NPECs were cultured and treated with verteporfin (VP), a selective YAP inhibitor, YAP shRNA or BAY 11-7082, a small molecule inhibitor of NF-κB. The relationship between cell proliferation and hippo pathway activity was explored using a cell counting kit-8 (CCK-8) assay, 5(6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) labelling and colony formation assay. The cell cycle and apoptosis were examined through flow cytometry (FCM) assay. The epithelium-derived cytokines including interleukin (IL-) 33, IL-25 and thymic stromal lymphopoietin(TSLP) were detected by RT-qPCR.Results: The hippo pathway effector YAP, Ki-67, p65 NF-κB, and cyclin D1were significantly increased in CRSwNP compared with control mucosa; which was accompanied by overexpression of interleukin (IL)-33, IL-25, and thymic stromal lymphopoieth (TSLP). Pharmaceutical inhibition of YAP by VP suppressed cell proliferation of RPMI 2650 cells by blocking cell cycle progression at G0/G1 without inducing obvious cell apoptosis. Furthermore, lentiviral transfection-mediated knockdown of hippo pathway activity reduced the expression of IL-33,,IL-25, TSLP as well as p65 NF-κB in RPMI 2650 cells. Downregulation of NF-κB pathway with BAY 11-7082 in NPECs could decrease the mRNA level of TSLP, IL-33 and IL-25 accordingly.Conclusions: Inhibition of hippo pathway suppressednasal epithelial cell proliferation and declined the expression of epithelium-derived cytokines IL-33 and IL-25 and TSLP expression via the NF-κB signalling pathway in NPECs.

scholarly journals Neutrophil Suppresses Tumor Cell Proliferation via Fas /Fas Ligand Pathway Mediated Cell Cycle Arrested

2018 ◽  
Vol 14 (14) ◽  
pp. 2103-2113 ◽  
Author(s):  
Bingwei Sun ◽  
Weiting Qin ◽  
Mingming Song ◽  
Lu Liu ◽  
Yao Yu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Cell ◽  
Fas Ligand ◽  
Tumor Cell Proliferation

Enzastaurin a protein kinase Cbeta-selective inhibitor, inhibits the growth of SCLC and NSCLC cell lines

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13138-13138 ◽  
Author(s):  
E. Nakajima ◽  
B. Helfrich ◽  
D. Chan ◽  
Z. Zhang ◽  
F. R. Hirsch ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Cell ◽  
Growth Inhibition ◽  
Cell Lines ◽  
Selective Inhibitor ◽  
Nsclc Cell ◽  
Tumor Cell Proliferation ◽  
Potential Synergy

13138 Background: PKCβ is a member of the PKC family of serine-threonine protein kinases involved in tumor cell proliferation and apoptosis. Inhibition of PKCs induced differentiation and enhanced chemotherapy. PKCβ activation is required for tumor-induced angiogenesis. The PKCβ-selective inhibitor enzastaurin, originally developed as an antiangiogenic agent, inhibited tumor cell proliferation in prostate, colon and glioblastoma cell lines in vitro. In NSCLC lines, enhanced phosphorylation and altered PKC expression was demonstrated. In SCLC lines specific PKC isoforms were associated with cisplatin resistance. Methods: The growth inhibitory effects of enzastaruin were evaluated by 6-day MTT assays; the cell cycle effects by FACS analysis; the effects on downstream phophorylated signaling molecules by western blotting. Results: Enzastaurin inhibited the growth of 11 SCLC lines (IC50s 3–10 μM) and 4 NSCLC cell lines (IC50s 3–10 μM). An increase of 7–31% of cells in the G2/M phase of the cell cycle compared to untreated control was observed following 48 hour exposure to the IC50 dose of enzastaurin in both SCLC and NSCLC cell lines. PKCβ has been shown to phosphorylate both GSK3β and Akt. A 24-hour IC50 enzastaurin exposure significantly reduced phosphorylation of GSK3β (Ser9) in both SCLC and NSCLC lines. No changes were observed in phospho-AKT (Thr308) in either SCLC or NSCLC cell lines. Phospho-ribosomal protein S6 (Ser240/244) was also reduced in both SCLC and NSCLC cell lines. Potential synergy was studied between enzastaurin and pemetrexed in SCLC and NSCLC lines and the results were analyzed using the Calcusyn Program by Chou and Talalay. Synergistic (CI <1) to additive interactions were observed between pemetrexed (IC20–70) and enzastaurin (≤ IC50) in both SCLC lines (N = 3) and NSCLC lines (N = 2). Conclusions: We conclude that enzastaruin produces in vitro growth inhibition of SCLC and NSCLC cell lines through inhibition of GSK3β ser9 phosphorylation and has synergistic growth inhibition with pemetrexed. [Table: see text]

scholarly journals Role for Histone Deacetylase 1 in Human Tumor Cell Proliferation

2007 ◽  
Vol 27 (13) ◽  
pp. 4784-4795 ◽  
Author(s):  
Silvia Senese ◽  
Katrin Zaragoza ◽  
Simone Minardi ◽  
Ivan Muradore ◽  
Simona Ronzoni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Cell ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Class I ◽  
Tumor Cell Proliferation ◽  
Specific Target ◽  
Class I Hdacs

ABSTRACT Posttranslational modifications of core histones are central to the regulation of gene expression. Histone deacetylases (HDACs) repress transcription by deacetylating histones, and class I HDACs have a crucial role in mouse, Xenopus laevis, zebra fish, and Caenorhabditis elegans development. The role of individual class I HDACs in tumor cell proliferation was investigated using RNA interference-mediated protein knockdown. We show here that in the absence of HDAC1 cells can arrest either at the G1 phase of the cell cycle or at the G2/M transition, resulting in the loss of mitotic cells, cell growth inhibition, and an increase in the percentage of apoptotic cells. On the contrary, HDAC2 knockdown showed no effect on cell proliferation unless we concurrently knocked down HDAC1. Using gene expression profiling analysis, we found that inactivation of HDAC1 affected the transcription of specific target genes involved in proliferation and apoptosis. Furthermore, HDAC2 downregulation did not cause significant changes compared to control cells, while inactivation of HDAC1, HDAC1 plus HDAC2, or HDAC3 resulted in more distinct clusters. Loss of these HDACs might impair cell cycle progression by affecting not only the transcription of specific target genes but also other biological processes. Our data support the idea that a drug targeting specific HDACs could be highly beneficial in the treatment of cancer.

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