This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Guerreiro, A. S. Articles by Arcaro, A. Search for Related Content PubMed PubMed Citation Articles by Guerreiro, A. S. Articles by Arcaro, A.

Targeting the PI3K p110 Isoform Inhibits Medulloblastoma Proliferation, Chemoresistance, and Migration

Authors' Affiliations: ¹ Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland; ² Laboratoire de Pathologie Moléculaire des Cancers, Institut Curie, Paris, France; ³ Unité d'Hématologie et Oncologie Pédiatrique, Centre Hospitalier Universitaire Vaudois Lausanne, Lausanne, Switzerland; and ⁴ Australian Centre for Blood Diseases, Monash University, Prahran, Victoria, Australia

Requests for reprints: Alexandre Arcaro, Department of Oncology, University Children's Hospital Zurich, August Forel-Strasse 1, Room 105, CH-8008 Zurich, Switzerland. Phone: 41-44-634-8921; Fax: 41-44-634-8859; 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 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 tumour samples and cell lines. Effects on cell survival and downstream signaling were analyzed following down-regulation of p110, p110β, or p110 by means of RNA interference or inhibition with isoform-specific PI3K inhibitors.

Results: Overexpression of the catalytic p110 isoform was detected in a panel of primary medulloblastoma samples and cell lines compared with normal brain tissue. Down-regulation of p110 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 p110β or p110 did not result in a comparable impairment of DAOY cell survival. Isoform-specific p110inhibitors also impaired medulloblastoma cell proliferation and sensitized the cells to chemotherapy. Medulloblastoma cells treated with p110 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 in medulloblastoma growth and survival.

This article has been cited by other articles:

				K.-T. Kuo, T.-L. Mao, S. Jones, E. Veras, A. Ayhan, T.-L. Wang, R. Glas, D. Slamon, V. E. Velculescu, R. J. Kuman, et al. Frequent Activating Mutations of PIK3CA in Ovarian Clear Cell Carcinoma Am. J. Pathol., May 1, 2009; 174(5): 1597 - 1601. [Abstract] [Full Text] [PDF]