Targeting the phosphoinositide 3-kinase p110-α isoform impairs cell proliferation, survival, and tumor growth in small cell lung cancer.

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 I(A) PI3K isoforms in small cell lung 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 downregulation by siRNA.

RESULTS:

Overexpression of the PI3K isoforms p110-α and p110-β and the antiapoptotic protein Bcl-2 was shown by immunohistochemistry in primary SCLC tissue samples. Targeting the PI3K p110-α with RNA interference or selective pharmacologic inhibitors resulted in strongly affected cell proliferation of SCLC cells in vitro and in vivo, whereas targeting p110-β was less effective. Inhibition of p110-α also resulted in increased apoptosis and autophagy, which was accompanied by decreased phosphorylation of Akt and components of the mTOR pathway, such as the ribosomal S6 protein, and the eukaryotic translation initiation factor 4E-binding protein 1. A DNA microarray analysis revealed that p110-α inhibition profoundly affected the balance of pro- and antiapoptotic Bcl-2 family proteins. Finally, p110-α inhibition led to impaired SCLC tumor formation and vascularization in vivo.

CONCLUSION:

Together our data show the key involvement of the PI3K isoform p110-α in the regulation of multiple tumor-promoting processes in SCLC.

• Authors: Anna Wojtalla, Barbara Fischer, Nataliya Kotelevets, Francesco A Mauri, Jens Sobek, Hubert Rehrauer, Carlos Wotzkow, Mario P Tschan, Michael J Seckl, Uwe Zangemeister-Wittke, Alexandre Arcaro
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 1 Pg. 96-105 (Jan 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23172887 (Publication Type: Journal Article)

Chemical References

• Isoenzymes
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Class Ia Phosphatidylinositol 3-Kinase
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Animals
• Apoptosis (genetics)
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Chick Embryo
• Class Ia Phosphatidylinositol 3-Kinase (genetics, metabolism)
• Gene Expression Profiling
• Humans
• Isoenzymes (antagonists & inhibitors, genetics, metabolism)
• Lung Neoplasms (enzymology, genetics, metabolism)
• Neovascularization, Pathologic (genetics)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• RNA Interference
• Signal Transduction
• Small Cell Lung Carcinoma (enzymology, genetics, metabolism)
• TOR Serine-Threonine Kinases (metabolism)