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Targeting the phosphoinositide 3-kinase isoform p110delta impairs growth and survival in neuroblastoma cells


Boller, D; Schramme, A; Doepfner, K T; Shalaby, T; von Bueren, A O; Eggert, A; Grotzer, M A; Arcaro, A (2008). Targeting the phosphoinositide 3-kinase isoform p110delta impairs growth and survival in neuroblastoma cells. Clinical Cancer Research, 14(4):1172-1181.

Abstract

PURPOSE: The phosphoinositide 3-kinase (PI3K)/Akt pathway is frequently activated in human cancer and plays a crucial role in neuroblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K/Akt signaling as a novel antiproliferative approach in neuroblastoma. EXPERIMENTAL DESIGN: The expression pattern and functions of class I(A) PI3K isoforms were investigated in tumor samples and cell lines. Effects on cell survival and downstream signaling were analyzed following down-regulation of p110alpha or p110delta in SH-SY5Y and LA-N-1 cells by means of RNA interference. RESULTS: Overexpression of the catalytic p110delta and regulatory p85alpha isoforms was detected in a panel of primary neuroblastoma samples and cell lines, compared with normal adrenal gland tissue. Although down-regulation of either p110alpha or p110delta led to impaired cell growth, reduced expression of p110delta also had a selective effect on the survival of SH-SY5Y cells. Decreased levels of p110delta were found to induce apoptosis and lead to lower expression levels of antiapoptotic Bcl-2 family proteins. SH-SY5Y cells with decreased p110delta levels also displayed reduced activation of ribosomal protein S6 kinase in response to stimulation with epidermal growth factor and insulin-like growth factor-I. CONCLUSIONS: Together, our data reveal a novel function of p110delta in neuroblastoma growth and survival.

PURPOSE: The phosphoinositide 3-kinase (PI3K)/Akt pathway is frequently activated in human cancer and plays a crucial role in neuroblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K/Akt signaling as a novel antiproliferative approach in neuroblastoma. EXPERIMENTAL DESIGN: The expression pattern and functions of class I(A) PI3K isoforms were investigated in tumor samples and cell lines. Effects on cell survival and downstream signaling were analyzed following down-regulation of p110alpha or p110delta in SH-SY5Y and LA-N-1 cells by means of RNA interference. RESULTS: Overexpression of the catalytic p110delta and regulatory p85alpha isoforms was detected in a panel of primary neuroblastoma samples and cell lines, compared with normal adrenal gland tissue. Although down-regulation of either p110alpha or p110delta led to impaired cell growth, reduced expression of p110delta also had a selective effect on the survival of SH-SY5Y cells. Decreased levels of p110delta were found to induce apoptosis and lead to lower expression levels of antiapoptotic Bcl-2 family proteins. SH-SY5Y cells with decreased p110delta levels also displayed reduced activation of ribosomal protein S6 kinase in response to stimulation with epidermal growth factor and insulin-like growth factor-I. CONCLUSIONS: Together, our data reveal a novel function of p110delta in neuroblastoma growth and survival.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2008
Deposited On:11 Feb 2009 17:07
Last Modified:05 Apr 2016 12:34
Publisher:American Association for Cancer Research
ISSN:1078-0432
Publisher DOI:10.1158/1078-0432.CCR-07-0737
PubMed ID:18281552
Permanent URL: http://doi.org/10.5167/uzh-5689

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