Targeting the Phosphoinositide 3-Kinase p110α Isoform Impairs Cell Proliferation, Survival and Tumor Growth in Small Cell Lung Cancer.

Wojtalla A, Fischer B, Kotelevets N, Mauri FA, Sobek J, Rehrauer H, Wotzkow C, Tschan M, Seckl MJ, Zangemeister-Wittke U, Arcaro A.

Source

Department of Clinical Research, University of Bern.

Abstract

PURPOSE:

The phosphoinositide 3-kinase (PI3K) pathway is fundamental for cell proliferation and survival and is frequently altered and activated in neoplasia, including carcinomas of the lung. In this study, we investigated the potential of targeting the catalytic class IA PI3K isoforms in small celllung cancer (SCLC), which is the most aggressive of all lung cancer types.

EXPERIMENTAL DESIGN:

The expression of PI3K isoforms in patient specimens was analyzed. The effects on SCLC cell survival and downstream signaling were determined following PI3K isoform inhibition by selective inhibitors or down-regulation by small interfering RNA.

RESULTS:

Over-expression of the PI3K isoforms p110α and p110β and the anti-apoptotic protein Bcl-2 was shown by immunohistochemistry in primary SCLC tissue samples. Targeting the PI3K p110α with RNA interference (RNAi) or selective pharmacological inhibitors resulted in strongly affected cell proliferation of SCLC cells in vitro and in vivo, while targeting p110β was less effective. Inhibition of p110α also resulted in increased apoptosis and autophagy, which was accompanied by decreased phosphorylation of Akt and components of the mammalian target of rapamycin (mTOR) pathway, such as the ribosomal S6 protein, and the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). A DNA microarray analysis revealed that p110α inhibition profoundly affected the balance of pro- and anti-apoptotic Bcl-2 family proteins. Finally, p110α inhibition led to impaired SCLC tumor formation and vascularization in vivo.

CONCLUSIONS:

Together our data demonstrate the key involvement of the PI3K isoform p110α in the regulation of multiple tumor-promoting processes in SCLC.

TimAllenMDJD

Friday, November 23, 2012