Targeting the PI3K p110α Isoform Inhibits Medulloblastoma Proliferation, Chemoresistance, and Migration

Purpose: The phosphoinositide 3-kinase (PI3K)/Akt pathway is frequently activated in human cancer and plays a crucial role in medulloblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K/Akt signaling as a novel antiproliferative approach in medulloblastoma. Experimental Design: The expression pattern and functions of class I-A PI3K isoforms were investigated in medulloblastoma turnout samples and cell lines. Effects on cell survival and downstream signaling were analyzed following down-regulation of p110 alpha, p110 beta, or p110 delta by means of RNA interference or inhibition with isoform-specific PI3K inhibitors. Results: Overexpression of the catalytic p110 alpha isoform was detected in a panel of primary medulloblastoma samples and cell lines compared with normal brain tissue. Down-regulation of p110 alpha expression by RNA interference impaired the growth of medulloblastoma cells, induced apoptosis, and led to decreased migratory capacity of the cells. This effect was selective, because RNA interference targeting of p110 beta or p110 delta did not result in a comparable impairment of DAOY cell survival. Isoform-specific p110 alpha inhibitors also impaired medulloblastoma cell proliferation and sensitized the cells to chemotherapy. Medulloblastoma cells treated with p110 alpha inhibitors further displayed reduced activation of Akt and the ribosomal protein S6 kinase in response to stimulation with hepatocyte growth factor and insulin-like growth factor-I. Conclusions: Together, our data reveal a novel function of p110 alpha in medulloblastoma growth and survival.