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Targeting the Phosphoinositide 3-Kinase Isoform p110 Impairs Growth and Survival in Neuroblastoma Cells

Authors' Affiliations: ¹ Division of Clinical Chemistry and Biochemistry and ² Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland; and ³ Department of Pediatric Oncology and Hematology, University Hospital of Essen, Essen, Germany

Requests for reprints: Alexandre Arcaro, Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland. Phone: 41-1-266-7640; Fax: 41-44-266-7169; E-mail: Alexandre.Arcaro{at}kispi.uzh.ch.

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 p110 or p110 in SH-SY5Y and LA-N-1 cells by means of RNA interference.

Results: Overexpression of the catalytic p110 and regulatory p85 isoforms was detected in a panel of primary neuroblastoma samples and cell lines, compared with normal adrenal gland tissue. Although down-regulation of either p110 or p110 led to impaired cell growth, reduced expression of p110 also had a selective effect on the survival of SH-SY5Y cells. Decreased levels of p110 were found to induce apoptosis and lead to lower expression levels of antiapoptotic Bcl-2 family proteins. SH-SY5Y cells with decreased p110 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 p110 in neuroblastoma growth and survival.