Suppression of proliferation of two independent NF1 malignant peripheral nerve sheath tumor cell lines by the pan-ErbB inhibitor CI-1033

Dilworth, J.T.; Wojtkowiak, Jonathan W.; Mathieu, Patricia; Tainsky, Michael A.; Reiners, John J.; Mattingly, Raymond R.; Hancock, Chad N.

doi:10.4161/cbt.7.12.6942

Cited by 13 publications

(10 citation statements)

References 53 publications

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“…STS-26T, NF90-8, and ST88-14 MPNST cell lines were generously donated by T. Glover (University of Michigan, Ann Arbor, MI). Maintenance of these cell lines was described previously (Dilworth et al, 2008;Wojtkowiak et al, 2008). In brief, adherent cultures were maintained in RPMI 1640 (Invitrogen, Carlsbad, CA) supplemented with 5% fetal bovine serum (HyClone Laboratories, Logan, UT), 100 U/ml penicillin, and 100 g/ml streptomycin (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

“…Of interest, although the NF90-8 and ST88-14 cell lines died by a caspase-dependent apoptotic pathway in the cotreatment protocol , preliminary studies indicated that STS-26T cells died by what appeared to be a nonapoptotic mechanism. Because currently available treatments are not effective for MPNSTs, investigation of new drug approaches to induce targeted cytotoxicity is needed (Dilworth et al, , 2008.…”

Section: Introductionmentioning

confidence: 99%

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Aborted Autophagy and Nonapoptotic Death Induced by Farnesyl Transferase Inhibitor and Lovastatin

Wojtkowiak

Sane

Kleinman

et al. 2011

The Journal of Pharmacology and Experimental Therapeutics

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Exposure of the human malignant peripheral nerve sheath tumor cell lines STS-26T, ST88-14, and NF90-8 to nanomolar concentrations of both lovastatin and farnesyl transferase inhibitor (FTI)-1 but not to either drug alone induced cell death. ST88-14 and NF90-8 cells underwent apoptosis, yet dying STS-26T cells did not. FTI-1 cotreatment induced a strong and sustained autophagic response as indicated by analyses of microtubule-associated protein-1 light chain 3 (LC3)-II accumulation in STS-26T cultures. Extensive colocalization of LC3-positive punctate spots was observed with both lysosomeassociated membrane protein (LAMP)-1 and LAMP-2 (markers of late endosomes/lysosomes) in solvent or FTI-1 or lovastatintreated STS-26T cultures but very little colocalization in lovastatin/FTI-1-cotreated cultures. The absence of colocalization in the cotreatment protocol correlated with loss of LAMP-2 expression. Autophagic flux studies indicated that lovastatin/ FTI-1 cotreatment inhibited the completion of the autophagic program. In contrast, rapamycin induced an autophagic response that was associated with cytostasis but maintenance of viability. These studies indicate that cotreatment of STS-26T cells with lovastatin and FTI-1 induces an abortive autophagic program and nonapoptotic cell death.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Aborted Autophagy and Nonapoptotic Death Induced by Farnesyl Transferase Inhibitor and Lovastatin

Wojtkowiak

Sane

Kleinman

et al. 2011

The Journal of Pharmacology and Experimental Therapeutics

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“…Previous work by the authors has shown that N-Ras as well as ERK1,2 is constitutively activated in two NF1-deficient MPNST cell lines [27]. One of these cell lines, ST88-14, has been used as a model to study the effectiveness of drugs with the potential of inhibiting tumor growth in NF1 patients [27–31]. …”

Section: Introductionmentioning

confidence: 99%

The role of neurofibromin in N-Ras mediated AP-1 regulation in malignant peripheral nerve sheath tumors

et al. 2010

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Plexiform neurofibromas commonly found in patients with Neurofibromatosis type I (NF1) have a 5% risk of being transformed into malignant peripheral nerve sheath tumors (MPNST). Germline mutations in the NF1 gene coding for neurofibromin, which is a Ras GTPase activating protein (RasGAP) and a negative regulator of Ras, result in an upregulation of the Ras pathway. We established a direct connection between neurofibromin deficiency and downstream effectors of Ras in cell lines from MPNST patients by demonstrating that knockdown of NF1 expression using siRNA in a NF1 wild type MPNST cell line, STS-26T, activates the Ras/ERK1,2 pathway and increases AP-1 binding and activity. We believe this is the first time the transactivation of AP-1 has been linked directly to neurofibromin deficiency in a disease relevant MPNST cell line. Previously, we have shown that N-Ras is constitutively activated in cell lines derived from independent MPNSTs from NF1 patients. We therefore sought to analyze the role of the N-Ras pathway in deregulating AP-1 transcriptional activity. We show that STS-26T clones conditionally expressing oncogenic N-Ras show increased phosphorylated ERK1,2 and phosphorylated JNK expression concomitant with increased AP-1 activity. MAP kinase pathways (ERK1,2 and JNK) were further examined in ST88-14, a neurofibromin-deficient MPNST cell line. The basal activity of ERK1,2 but not JNK was found to increase AP-1 activity. These experiments further confirmed the link between the loss of neurofibromin and increased activity of Ras/MAP kinase pathways and the activation of downstream transcriptional mechanisms in MPNSTs from NF1 patients.

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“…Finally, to confirm the involvement of ErbB receptors in the action of NRG-1, we used two different pan-ErbB inhibitors (C39 and CI-1033) (Ako et al, 2007;Dilworth et al, 2008;Klutchko et al, 2006) to see if they would reverse the effect of NRG-1 in HEM-DP and/or in dark MelanoDerms. C39 (0.5 mM) or CI-1033 (2 mM) alone did not affect the melanin content of HEM-DP, 3106 Journal of Cell Science 123 (18) whereas NRG-1 alone stimulated melanin content as expected (Fig.…”

Section: Nrg-1 Receptors Expressed By Human Melanocytesmentioning

confidence: 99%

The fibroblast-derived paracrine factor neuregulin-1 has a novel role in regulating the constitutive color and melanocyte function in human skin

Choi

Wolber

Gerwat

et al. 2010

Journal of Cell Science

102

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SummaryInteractions between melanocytes and neighboring cells in the skin are important in regulating skin color in humans. We recently demonstrated that the less pigmented and thicker skin on the palms and soles is regulated by underlying fibroblasts in those areas, specifically via a secreted factor (DKK1) that modulates Wnt signaling. In this study, we tested the hypothesis that dermal fibroblasts regulate the constitutive skin color of individuals ranging from very light to very dark. We used microarray analysis to compare gene expression patterns in fibroblasts derived from lighter skin types compared to darker skin types, with a focus on secreted proteins. We identified a number of genes that differ dramatically in expression and, among the expressed proteins, neuregulin-1, which is secreted by fibroblasts derived from dark skin, effectively increases the pigmentation of melanocytes in tissue culture and in an artificial skin model and regulates their growth, suggesting that it is one of the major factors determining human skin color.

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Suppression of proliferation of two independent NF1 malignant peripheral nerve sheath tumor cell lines by the pan-ErbB inhibitor CI-1033

Cited by 13 publications

References 53 publications

Aborted Autophagy and Nonapoptotic Death Induced by Farnesyl Transferase Inhibitor and Lovastatin

Aborted Autophagy and Nonapoptotic Death Induced by Farnesyl Transferase Inhibitor and Lovastatin

The role of neurofibromin in N-Ras mediated AP-1 regulation in malignant peripheral nerve sheath tumors

The fibroblast-derived paracrine factor neuregulin-1 has a novel role in regulating the constitutive color and melanocyte function in human skin

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