Novel interferon-λs induce antiproliferative effects in neuroendocrine tumor cells

Zitzmann, Kathrin; Brand, Stephan; Baehs, Sebastian; Göke, Burkhard; Meinecke, Jennifer; Spöttl, Gerald; Meyer, Heinrich H.H.D.; Auernhammer, Christoph J.

doi:10.1016/j.bbrc.2006.04.043

Cited by 109 publications

(90 citation statements)

References 26 publications

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“…Protein extraction and western blotting were performed as described previously in detail (Zitzmann et al 2006). Primary antibodies used were pAkt (Ser473; …”

Section: Invasion Assaymentioning

confidence: 99%

Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

Zitzmann

Vlotides²,

Brand³

et al. 2012

Endocrine-Related Cancer

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The majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system show aberrant Akt activity. Several inhibitors of the phosphoinositide 3-kinase (PI(3)K)-Akt-mTOR signaling pathway are currently being evaluated in clinical phase II and III studies for the treatment of NETs with promising results. However, the molecular mechanisms and particularly the role of different Akt isoforms in NET signaling are not fully understood. In this study, we examine the effect of Akt inhibition on NET cells of heterogeneous origin. We show that the Akt inhibitor perifosine effectively inhibits Akt phosphorylation and cell viability in human pancreatic (BON1), bronchus (NCI-H727), and midgut (GOT1) NET cells. Perifosine treatment suppressed the phosphorylation of Akt downstream targets such as GSK3a/b, MDM2, and p70S6K and induced apoptosis. To further investigate the role of individual Akt isoforms for NET cell function, we specifically blocked Akt1, Akt2, and Akt3 via siRNA transfection. In contrast to Akt2 knockdown, knockdown of Akt isoforms 1 and 3 decreased phosphorylation levels of GSK3a/b, MDM2, and p70S6K and suppressed NET cell viability and colony-forming capacity. The inhibitory effect of simultaneous downregulation of Akt1 and Akt3 on tumor cell viability was significantly stronger than that caused by downregulation of all Akt isoforms, suggesting a particular role for Akt1 and Akt3 in NET signaling. Akt3 siRNA-induced apoptosis while all three isoform-specific siRNAs impaired BON1 cell invasion. Together, our data demonstrate potent antitumor effects of the panAkt inhibitor perifosine on NET cells in vitro and suggest that selective targeting of Akt1 and/or Akt3 might improve the therapeutic potential of Akt inhibition in NET disease.

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“…Protein extraction and western blotting were performed as described previously in detail (Zitzmann et al 2006). Primary antibodies used were pAkt (Ser473; …”

Section: Invasion Assaymentioning

confidence: 99%

Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

Zitzmann

Vlotides²,

Brand³

et al. 2012

Endocrine-Related Cancer

Self Cite

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“…p53 is a transcription factor whose activity gives rise to a variety of cellular outcomes, most notably cell cycle arrest and apoptosis, eliminating cancer-prone cells from the replicative pool (46). IFN-Ïs were found to inhibit tumor growth in vitro and in vivo (13)(14)(15)(16). Moreover, the expressions of IFN-Ïs are indeed related to the cancer prognosis in some cancer (19).…”

Section: Discussionmentioning

confidence: 99%

“…Another important property of IFN-Ïs is their potential anti-proliferative activities inhibiting the growth of the human glioblastoma LN319 cell line (13), human neuroendocrine BON1 tumor cells (14), human keratinocyte cell line HaCaT (15), human fibrosarcoma 2fTGH cell line (16) and murine BW5147 thymoma cell line (16). These effects of IFN-Ïs were fulfilled by the IFN-Ï receptor complex that leads to the activation of signal transducers and activators of transcription (STAT)1 and STAT2, which, together with IFN regulatory factor-9, form a transcriptional complex called IFNstimulated gene factor-3.1,7,9 (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Integrative genomic analyses on IL28RA, the common receptor of interferon-λ1, -λ2 and -λ3

Yang

Luo²,

Wei³

et al. 2010

Int J Mol Med

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Abstract. Interferon (IFN)-Ïs, including INF-Ï1, -Ï2, and -Ï3, are a newly described group of cytokines distantly related to the type I IFNs and IL-10 family members. IFN-Ï1, -Ï2, and -Ï3 bind to the same receptor (known as IL28RA) to exert their antiviral, antitumor and immunomodulatory effects. Here, we identified IL28RA genes from the genome of human, chimpanzee, macaque, orangutan, mouse, horse, rat, dog, chicken, and found that only one IL28RA existed in each genome. All the identified IL28RAs are single-pass type I membrane proteins except chicken IL28RA. They belong to the type II cytokine receptor family and contain one fibronectin type-III domain. We found human IL28RA was expressed in lymphs, testes, lymphoma, teratocarcinoma, pediatric pre-B cell acute lymphoblastic leukemia, germinal center B cells, embryonic stem cells, fetal lung, and also expressed in bladder, blood and breast cancers, glioma, head and neck cancer and lung cancer tissues. Three tumor-related transcriptional factor binding sites (AP-2, c-Jun and P53) were identified within the 1.0-kb regions upstream of the transcriptional start site of human IL28RA. Meta-analysis of the prognostic value of IL28RA genes in various cancers found that the expression of IL28RA was indeed related to the cancer prognosis in certain cancers. The STAT1 binding sites in the promoter region of IL28RA implied a specific mechanism for the amplifying effects of IFN-Ïs. The LyF-1 binding sites in the promoter region of IL28RA imply that IFN-Ïs were involved in the differentiation of early B and T cells.

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“…Protein extraction and western blotting were done as previously described in detail (Zitzmann et al 2006). Primary antibodies used were PARP, caspase-3, cleaved caspase-3, caspase-8, cleaved caspase-9, Bcl-XL, Bid (Cell Signaling, Danvers, MA, USA), Bcl-2 (BD, Franklin Lakes, NJ, USA), and b-actin (Abcam, Cambridge, UK).…”

Section: Protein Extraction and Western Blottingmentioning

confidence: 99%

The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells

Zitzmann

Toni²,

Rüden³

et al. 2011

Endocrine Related Cancer

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The tumour-selective death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for the treatment of human cancer. However, many tumours have evolved mechanisms to resist TRAIL-induced apoptosis. A number of studies have demonstrated that aberrant PI(3)K-Akt-mTOR survival signalling may confer TRAIL resistance by altering the balance between pro-and anti-apoptotic proteins. Here, we show that neuroendocrine tumour (NET) cell lines of heterogeneous origin exhibit a range of TRAIL sensitivities and that TRAIL sensitivity correlates with the expression of FLIP S , caspase-8, and Bcl-2. Neither single mTOR inhibition by everolimus nor dual mTOR/PI(3)K inhibition by NVP-BEZ235 was able to enhance TRAIL susceptibility in any of the tested cell lines. In contrast, dual PI(3)K-Akt-mTOR and Raf-MEK-Erk pathway inhibition by the IGF-1R inhibitor NVP-AEW541 effectively restored TRAIL sensitivity in NCI-H727 bronchus carcinoid cells. Furthermore, blocking Raf-MEK-Erk signalling by the novel Raf inhibitor Raf265 significantly enhanced TRAIL sensitivity in NCI-H727 and CM insulinoma cells. While having no effect on FLIP S or caspase-8 expression, Raf265 strongly decreased Bcl-2 levels in those cell lines susceptible to its TRAIL-sensitizing action. Taken together, our findings suggest that combinations of Raf-MEK-Erk pathway inhibitors and TRAIL might offer a novel therapeutic strategy in NET disease.

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Novel interferon-λs induce antiproliferative effects in neuroendocrine tumor cells

Cited by 109 publications

References 26 publications

Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

Integrative genomic analyses on IL28RA, the common receptor of interferon-λ1, -λ2 and -λ3

The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells

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