Targeting the phosphoinositide 3-kinase isoform p110δ impairs growth and survival in neuroblastoma cells

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 alpha or p110 delta in SH-SY5Y and LA-N-1 cells by means of RNA interference. Results: Overexpression of the catalytic p110 delta and regulatory p85 alpha 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 alpha or p110 delta led to impaired cell growth, reduced expression of p110 delta also had a selective effect on the survival of SH-SY5Ycells. Decreased levels of p110 delta were found to induce apoptosis and lead to lower expression levels of antiapoptotic Bcl-2 family proteins. SH-SY5Ycells with decreased p110 delta 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 delta in neuroblastoma growth and survival.