title: Targeting the phosphoinositide 3-kinase p110-α isoform impairs cell proliferation, survival, and tumor growth in small cell lung cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Together our data show the key involvement of the PI3K isoform p110-α in the regulation of multiple tumor-promoting processes in SCLC.
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wojtalla
authors.forename: Barbara
authors.initials: B
authors.lastname: Fischer
authors.forename: Nataliya
authors.initials: N
authors.lastname: Kotelevets
authors.forename: Francesco A
authors.initials: FA
authors.lastname: Mauri
authors.forename: Jens
authors.initials: J
authors.lastname: Sobek
authors.forename: Hubert
authors.initials: H
authors.lastname: Rehrauer
authors.forename: Carlos
authors.initials: C
authors.lastname: Wotzkow
authors.forename: Mario P
authors.initials: MP
authors.lastname: Tschan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seckl
authors.forename: Uwe
authors.initials: U
authors.lastname: Zangemeister-Wittke
authors.forename: Alexandre
authors.initials: A
authors.lastname: Arcaro
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002642:Chick Embryo; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D055752:Small Cell Lung Carcinoma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases