Novel cross talk between MEK and S6K2 in FGF-2 induced proliferation of SCLC cells

Pardo, Olivier E.; Arcaro, Alexandre; Salerno, Giovanni; Tetley, Teresa D.; Valovka, Taras; Gout, Ivan; Seckl, Michael J.

doi:10.1038/sj.onc.1204994

Cited by 66 publications

(85 citation statements)

References 43 publications

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“…The immunosuppressive macrolide rapamycin, the most potent inhibitor of mTOR, can inhibit S6K activation independent of phosphoinositide 3-kinase signaling (4,(31)(32)(33). Our experiments suggested, as in previous studies, that mTOR may respond to mitogenic signals (34).…”

Section: Discussionsupporting

confidence: 72%

Autocrine Transforming Growth Factor α Regulates Cell Adhesion by Multiple Signaling via Specific Phosphorylation Sites of p70S6 Kinase in Colon Cancer Cells

Sawhney

Cookson

Sharma

et al. 2004

Journal of Biological Chemistry

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Recently, we showed that autocrine transforming growth factor ␣ (TGF␣) controls the epidermal growth factor receptor (EGFR)-mediated basal expression of integrin ␣ 2 , cell adhesion and motility in highly progressed HCT116 colon cancer cells. We also reported that the expression of basal integrin ␣ 2 and its biological effects are critically controlled by the constitutive activation of the ERK/MAPK pathway (Sawhney, R. S., Sharma, B., Humphrey, L. E., and Brattain, M. G. (2003)

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Section: Discussionsupporting

confidence: 72%

Autocrine Transforming Growth Factor α Regulates Cell Adhesion by Multiple Signaling via Specific Phosphorylation Sites of p70S6 Kinase in Colon Cancer Cells

Sawhney

Cookson

Sharma

et al. 2004

Journal of Biological Chemistry

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“…Under this condition, increased cell proliferation in response to SCF was observed in H-69 but not in H-209 cells (Figure 2b), as previously reported . Since MEK/Erk signalling has been shown to be critical for SCLC cell growth in response to polypeptide growth factor stimulation (Pardo et al, 2001), we tested the impact of the specific MEK inhibitor PD098059 on H-69 growth in liquid culture. The inhibitor blocked basal and SCF-stimulated H-69 SCLC cell proliferation in serum-free medium (data not shown), which supports the model that Ras signalling to MEK/Erk is essential for SCLC proliferation.…”

Section: Simvastatin Inhibits Sclc Cell Growth In Vitromentioning

confidence: 99%

“…Polypeptide growth factors such as stem cell factor (SCF) and fibroblast growth factor-2 (FGF-2) induce a variety of responses in human SCLC cells, including growth and proliferation, chemoresistance and motility (Heasley, 2001;Pardo et al, 2001Pardo et al, , 2002Arcaro et al, 2002). Activation of two major intracellular signalling pathways, the mitogen-activated Erk kinase (MEK)/ extracellular signal-regulated kinase (Erk) and phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) pathways have been shown to mediate SCLC responses to polypeptide growth factors and thus represent attractive targets for the development of new drugs targeting SCLC in patients (Pardo et al, 2001(Pardo et al, , 2002Arcaro et al, 2002;Krystal et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Activation of two major intracellular signalling pathways, the mitogen-activated Erk kinase (MEK)/ extracellular signal-regulated kinase (Erk) and phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) pathways have been shown to mediate SCLC responses to polypeptide growth factors and thus represent attractive targets for the development of new drugs targeting SCLC in patients (Pardo et al, 2001(Pardo et al, , 2002Arcaro et al, 2002;Krystal et al, 2002). Indeed, recent studies have reported that interfering with PKB, ribosomal protein S6 kinase (S6K) and MEK/Erk activation results in negative effects on SCLC growth and chemoresistance (Moore et al, 1998;Pardo et al, 2001Pardo et al, , 2002Arcaro et al, 2002;Krystal et al, 2002). Since Ras family proteins transduce receptor tyrosine kinase signals to both the Erk and PI3K signalling cascades, inhibiting their function in SCLC cells may have a negative impact on tumour cell proliferation and survival.…”

Section: Introductionmentioning

confidence: 99%

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Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling

Pardo²,

et al. 2005

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The impact of the 3-hydroxy-3methylglutaryl CoA reductase inhibitor simvastatin on human small-cell lung cancer (SCLC) cell growth and survival was investigated. Simvastatin profoundly impaired basal and growth factorstimulated SCLC cell growth in vitro and induced apoptosis. SCLC cells treated with simvastatin were sensitized to the effects of the chemotherapeutic agent etoposide. Moreover, SCLC tumour growth in vivo was inhibited by simvastatin. These responses correlated with the inhibition of stem cell factor (SCF)-stimulated activation of extracellular signal-regulated kinase (Erk), protein kinase B (PKB) and ribosomal S6 kinase by simvastatin. Constitutive activation of the Erk pathway was sufficient to rescue SCLC cell from the effects of simvastatin. The drug did not directly affect activation of c-Kit or its localization to lipid rafts, but in addition to its ability to block Ras membrane localization, it selectively downregulated H-Ras protein levels at the post-translational level. Downregulation of either H-or K-Ras by RNA interference (RNAi) did not impair Erk activation by growth factors, whereas an RNAi specific for N-Ras inhibited activation of Erk, PKB and SCLC cell growth. Together our data demonstrate that inhibiting Ras signalling with simvastatin potently disrupts growth and survival in human SCLC cells.

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“…In the past years, an increasing number of molecular alterations involved in SCLC pathogenesis have been reported, including ectopic expression of neuroendocrine regulatory peptides, upregulation of antiapoptotic Bcl-2 proteins, overexpression of myc family oncogenes and extracellular matrix proteins, as well as genetic abnormalities in the tumor suppressor genes TP53 and RB (1,2). In addition, it has been shown that polypeptide growth factors such as hepatocyte growth factor (HGF), fibroblast growth factor-2 (FGF-2), insulin-like growth factor-1 (IGF-1), and stem cell factor (SCF) control key biologic responses in human SCLC cells, including growth and proliferation, chemoresistance, and migration (3)(4)(5)(6). Downstream of activated polypeptide growth factor receptors, activation of 2 major intracellular signaling cascades, the phosphoinositide-3 kinase (PI3K)/ Akt/mTOR, and the mitogen-activated Erk kinase (MEK)/ extracellular signal-regulated kinase (ERK) pathway, have been found to be involved in the survival and proliferation of SCLC (3,(5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Targeting the Phosphoinositide 3-Kinase p110-α Isoform Impairs Cell Proliferation, Survival, and Tumor Growth in Small Cell Lung Cancer

Wojtalla

Fischer

Kotelevets

et al. 2013

Clinical Cancer Research

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Purpose: The phosphoinositide 3-kinase (PI3K) pathway is fundamental for cell proliferation and survival and is frequently altered and activated in neoplasia, including carcinomas of the lung. In this study, we investigated the potential of targeting the catalytic class I A PI3K isoforms in small cell lung cancer (SCLC), which is the most aggressive of all lung cancer types.Experimental Design: The expression of PI3K isoforms in patient specimens was analyzed. The effects on SCLC cell survival and downstream signaling were determined following PI3K isoform inhibition by selective inhibitors or downregulation by siRNA.Results: Overexpression of the PI3K isoforms p110-a and p110-b and the antiapoptotic protein Bcl-2 was shown by immunohistochemistry in primary SCLC tissue samples. Targeting the PI3K p110-a with RNA interference or selective pharmacologic inhibitors resulted in strongly affected cell proliferation of SCLC cells in vitro and in vivo, whereas targeting p110-b was less effective. Inhibition of p110-a also resulted in increased apoptosis and autophagy, which was accompanied by decreased phosphorylation of Akt and components of the mTOR pathway, such as the ribosomal S6 protein, and the eukaryotic translation initiation factor 4E-binding protein 1. A DNA microarray analysis revealed that p110-a inhibition profoundly affected the balance of pro-and antiapoptotic Bcl-2 family proteins. Finally, p110-a inhibition led to impaired SCLC tumor formation and vascularization in vivo.Conclusion: Together our data show the key involvement of the PI3K isoform p110-a in the regulation of multiple tumor-promoting processes in SCLC.

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Novel cross talk between MEK and S6K2 in FGF-2 induced proliferation of SCLC cells

Cited by 66 publications

References 43 publications

Autocrine Transforming Growth Factor α Regulates Cell Adhesion by Multiple Signaling via Specific Phosphorylation Sites of p70S6 Kinase in Colon Cancer Cells

Autocrine Transforming Growth Factor α Regulates Cell Adhesion by Multiple Signaling via Specific Phosphorylation Sites of p70S6 Kinase in Colon Cancer Cells

Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling

Targeting the Phosphoinositide 3-Kinase p110-α Isoform Impairs Cell Proliferation, Survival, and Tumor Growth in Small Cell Lung Cancer

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