title: Phosphatidylinositol 3-kinase, class 2 beta (PI3KC2β) isoform contributes to neuroblastoma tumorigenesis.
abstract: Phosphatidylinositol 3-kinases (PI3Ks) play important roles in human tumorigenesis. Activation of the PI3K target AKT is frequent in neuroblastoma (NB) and correlates with poor prognosis. PI3K pan-inhibitors reduce NB tumor formation but present severe toxicity, which limits their therapeutic potential. Therefore, defining the importance of specific PI3K isoforms may aid in developing more effective therapeutic strategies. We previously demonstrated that PI3K Class IIβ (PI3KC2β) and its regulator intersectin 1 (ITSN1) are highly expressed in primary NB tumors and cell lines. Silencing ITSN1 dramatically reduced the tumorigenic potential of NB cells. Interestingly, overexpression of PI3KC2β rescued the anchorage-independent growth of ITSN1-silenced cells suggesting that PI3KC2β mediates ITSN1's function in NB cells. To address the importance of PI3KC2β in NBs, we generated PI3KC2β-silenced lines and examined their biologic activity. Herein, we demonstrate that PI3KC2β-silencing inhibits early stages of NB tumorigenic growth. We also show that loss of endogenous PI3KC2β or ITSN1 reduces AKT activation but does not impact ERK-MAPK activation. These data reveal a novel role for PI3KC2β in human NB tumorigenesis.
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612.
authors.forename: Angela
authors.initials: A
authors.lastname: Russo
authors.affiliation: Department of Biochemistry, University of Illinois at Chicago, Chicago, IL 60612.
authors.forename: Mustafa Nazir
authors.initials: MN
authors.lastname: Okur
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612; University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612.
authors.forename: Maarten
authors.initials: M
authors.lastname: Bosland
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612; University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612; Jesse Brown VA Medical Center, Chicago, IL 60612. Electronic address: obryanj@uic.edu.
authors.forename: John P
authors.initials: JP
authors.lastname: O'Bryan
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058541:Class II Phosphatidylinositol 3-Kinases; D055785:Gene Knockdown Techniques; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D020935:MAP Kinase Signaling System; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C485568:ITSN1 protein, human; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D058541:Class II Phosphatidylinositol 3-Kinases; C502616:PIK3C2B protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; ITSN1; Neuroblastoma; Oncogenesis; PIK3C2β; Pediatric tumors