title: Signaling networks associated with AKT activation in non-small cell lung cancer (NSCLC): new insights on the role of phosphatydil-inositol-3 kinase.
abstract: Aberrant activation of PI3K/AKT signalling represents one of the most common molecular alterations in lung cancer, though the relative contribution of the single components of the cascade to the NSCLC development is still poorly defined. In this manuscript we have investigated the relationship between expression and genetic alterations of the components of the PI3K/AKT pathway [KRAS, the catalytic subunit of PI3K (p110α), PTEN, AKT1 and AKT2] and the activation of AKT in 107 surgically resected NSCLCs and have analyzed the existing relationships with clinico-pathologic features. Expression analysis was performed by immunohistochemistry on Tissue Micro Arrays (TMA); mutation analysis was performed by DNA sequencing; copy number variation was determined by FISH. We report that activation of PI3K/AKT pathway in Italian NSCLC patients is associated with high grade (G3-G4 compared with G1-G2; n = 83; p<0.05) and more advanced disease (TNM stage III vs. stages I and II; n = 26; p<0.05). In addition, we found that PTEN loss (41/104, 39%) and the overexpression of p110α (27/92, 29%) represent the most frequent aberration observed in NSCLCs. Less frequent molecular lesions comprised the overexpression of AKT2 (18/83, 22%) or AKT1 (17/96, 18%), and KRAS mutation (7/63, 11%). Our results indicate that, among all genes, only p110α overexpression was significantly associated to AKT activation in NSCLCs (p = 0.02). Manipulation of p110α expression in lung cancer cells carrying an active PI3K allele (NCI-H460) efficiently reduced proliferation of NSCLC cells in vitro and tumour growth in vivo. Finally, RNA profiling of lung epithelial cells (BEAS-2B) expressing a mutant allele of PIK3 (E545K) identified a network of transcription factors such as MYC, FOS and HMGA1, not previously recognised to be associated with aberrant PI3K signalling in lung cancer.
authors.affiliation: Biogem scarl, Institute for Genetic Research Gaetano Salvatore, Ariano Irpino (Avellino), Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Scrima
authors.forename: Carmela
authors.initials: C
authors.lastname: De Marco
authors.forename: Fernanda
authors.initials: F
authors.lastname: Fabiani
authors.forename: Renato
authors.initials: R
authors.lastname: Franco
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pirozzi
authors.forename: Gaetano
authors.initials: G
authors.lastname: Rocco
authors.forename: Maria
authors.initials: M
authors.lastname: Ravo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Weisz
authors.forename: Pietro
authors.initials: P
authors.lastname: Zoppoli
authors.forename: Michele
authors.initials: M
authors.lastname: Ceccarelli
authors.forename: Gerardo
authors.initials: G
authors.lastname: Botti
authors.forename: Donatella
authors.initials: D
authors.lastname: Malanga
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viglietto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010768:Phosphoserine / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D010768:Phosphoserine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins