Targeting the Phosphoinositide 3-Kinase Isoform p110δ Impairs Growth and Survival in Neuroblastoma Cells

Boller, Danielle; Schramm, Alexander; Doepfner, Kathrin T.; Shalaby, Tarek; Bueren, André O. von; Eggert, Angelika; Grotzer, Michael A.; Arcaro, Alexandre

doi:10.1158/1078-0432.ccr-07-0737

Cited by 66 publications

(59 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Overexpression of p110-d was found in a subset of primary neuroblastoma and cell lines, and p110-d was essential for signal transduction by receptor tyrosine kinases, such as the IGF-1R and EGF receptor (EGFR; ref. 28). In contrast, in SCLC cell lines, p110-a seems to play a more important role in the activation of the Akt/mTOR pathway, which may explain the impact of agents targeting this isoform on SCLC proliferation and survival.…”

Section: Discussionmentioning

confidence: 95%

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 95%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…To date, activating mutations of p110α have been found in a significant fraction of commonly occurring human cancers, whereas no somatic mutations have been identified in the other class IA isoforms p110β and p110δ (11,12). On the other hand, there are several cancer types that have been reported to have elevated levels and/or genomic amplifications of these other isoforms, indicating that they too may contribute to cancer (13,14). In addition, activation of receptor tyrosine kinases such as VEGF receptor, EGF receptor, PDGF receptor, or human epidermal growth factor receptor 2 (HER2) leading to the activation of the PI3K pathway usually requires p110α for signaling and tumorigenesis (15)(16)(17).…”

mentioning

confidence: 99%

PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context

Schmit

Utermark

Zhang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

There has been increasing interest in the use of isoform-selective inhibitors of phosphatidylinositide-3-kinase (PI3K) in cancer therapy. Using conditional deletion of the p110 catalytic isoforms of PI3K to predict sensitivity of cancer types to such inhibitors, we and others have demonstrated that tumors deficient of the phosphatase and tensin homolog (PTEN) are often dependent on the p110β isoform of PI3K. Because human cancers usually arise due to multiple genetic events, determining whether other genetic alterations might alter the p110 isoform requirements of PTEN-null tumors becomes a critical question. To investigate further the roles of p110 isoforms in PTEN-deficient tumors, we used a mouse model of ovarian endometrioid adenocarcinoma driven by concomitant activation of the rat sarcoma protein Kras, which is known to activate p110α, and loss of PTEN. In this model, ablation of p110β had no effect on tumor growth, whereas p110α ablation blocked tumor formation. Because ablation of PTEN alone is often p110β dependent, we wondered if the same held true in the ovary. Because PTEN loss alone in the ovary did not result in tumor formation, we tested PI3K isoform dependence in ovarian surface epithelium (OSE) cells deficient in both PTEN and p53. These cells were indeed p110β dependent, whereas OSEs expressing activated Kras with or without PTEN loss were p110α dependent. Furthermore, isoform-selective inhibitors showed a similar pattern of the isoform dependence in established Kras G12D /PTEN-deficient tumors. Taken together, our data suggest that, whereas in some tissues PTEN-null tumors appear to inherently depend on p110β, the p110 isoform reliance of PTEN-deficient tumors may be altered by concurrent mutations that activate p110α.ovarian cancer | PI3K inhibitors | genetically engineered mouse model

show abstract

“…19 Since the PI3K/Akt signaling pathway and its downstream molecules are activated in neuroblastomas, 5,6,20 we have investigated the effects of inhibitors of this pathway in vitro and in vivo.…”

mentioning

confidence: 99%

Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo

Segerström

Baryawno

Sveinbjørnsson

et al. 2011

Intl Journal of Cancer

View full text Add to dashboard Cite

Activation of the PI3K/Akt signaling pathway is correlated with poor prognosis in neuroblastoma, the most common and deadly extracranial tumor of childhood. In this study, we show that the small-molecule inhibitors of phosphoinositidedependent protein kinase-1 (PDK1) OSU03012 and the dual class I PI3K/mTOR inhibitor PI103 have profound effects on neuroblastoma survival in vitro and in vivo. Both OSU03012 and PI103 inhibited neuroblastoma growth in vitro. In treated cells, OSU03012 induced apoptosis and an S phase cell cycle arrest, whereas only minor apoptosis was detected in PI103 treated cells together with a G1 arrest. Both OSU03012 and PI103 downregulated phosphorylation of Akt and inhibited the downstream targets glycogen synthase kinase-3b (GSK3b) and p70 S6 kinase-1 (S6K1), as well as downregulated the expression of cyclin D1 and Mycn protein. Neuroblastoma cells expressing high levels of Mycn were more sensitive to OSU03012 or PI103 compared with cells expressing low Mycn levels. Both compounds significantly inhibited the growth of established, subcutaneous MYCN-amplified neuroblastoma xenografts in nude NMRI nu/nu mice. These results suggest that inhibition of the PI3K/Akt signaling pathway represent a clinical relevant target for the treatment of patients with high-risk MYCN-amplified neuroblastoma.Neuroblastomas are peripheral nervous system tumors that originate in the neural crest and are most commonly found in the adrenal medulla or along the sympathetic chain. 1 These tumors show heterogeneous biological and clinical features, in which a subset is prone to regress through spontaneous apoptosis with little or no therapy while another subset differentiates over time to benign ganglioneuromas. However, the majority of neuroblastomas are malignant with metastatic spread that is difficult to cure with current treatment modalities.2 Amplification of the MYCN gene, which occurs in 40-50% of the high-risk neuroblastoma cases, remains the major key predictor of poor outcome and is associated with advanced-stage disease, rapid tumor progression and low survival.3 Advanced-stage tumors and those with MYCN gene amplification typically show emergence of treatment resistance and new treatment alternatives for these patients are highly warranted.Abnormal activation of the PI3K/Akt signaling pathway is a common event in human cancers and has been validated through epidemiological and experimental studies as being essential for several human tumors, including neuroblastoma.4-6 PI3K is a family of lipid kinases, heterodimeric proteins composed of one catalytic and one regulatory subunit. In the class IA PI3Ks, there are currently three isoforms of the catalytic (p110a, b, and d) and five of the regulatory (p50a, p55a, p85a, p85b, and p55c) subunits, where p50a and p55a are splice variants of p85a. PI3Ks functions as signal transducers downstream of cell-surface receptors, such as receptor tyrosine kinases. Activated PI3Ks phosphorylate the lipid phosphatidyl-inositol 4,5-biphosphate (PIP2) to generate phosphatidyl-...

show abstract

Targeting the Phosphoinositide 3-Kinase Isoform p110δ Impairs Growth and Survival in Neuroblastoma Cells

Cited by 66 publications

References 38 publications

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

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

PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context

Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo

Contact Info

Product

Resources

About