Dataset Information

Phosphatidylinositol 3-kinase, class 2 beta (PI3KC2?) 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 II? (PI3KC2?) 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 PI3KC2? rescued the anchorage-independent growth of ITSN1-silenced cells suggesting that PI3KC2? mediates ITSN1's function in NB cells. To address the importance of PI3KC2? in NBs, we generated PI3KC2?-silenced lines and examined their biologic activity. Herein, we demonstrate that PI3KC2?-silencing inhibits early stages of NB tumorigenic growth. We also show that loss of endogenous PI3KC2? or ITSN1 reduces AKT activation but does not impact ERK-MAPK activation. These data reveal a novel role for PI3KC2? in human NB tumorigenesis.

SUBMITTER: Russo A

PROVIDER: S-EPMC4351744 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Phosphatidylinositol 3-kinase, class 2 beta (PI3KC2β) isoform contributes to neuroblastoma tumorigenesis.

Russo Angela A Okur Mustafa Nazir MN Bosland Maarten M O'Bryan John P JP

Cancer letters 20150123 2

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 regulato ...[more]

PMID: 25622909

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Project description:Rhinoviruses (RVs) replicate on cytoplasmic membranes derived from the Golgi apparatus. They encode membrane-targeted proteins 2B, 2C, and 3A, which control trafficking and lipid composition of the replication membrane. The virus recruits host factors for replication, such as phosphatidylinositol 4 (PI4)-kinase 3beta (PI4K3b), which boosts PI4-phosphate (PI4P) levels and drives lipid countercurrent exchange of PI4P against cholesterol at endoplasmic reticulum-Golgi membrane contact sites through the lipid shuttling protein oxysterol binding protein 1 (OSBP1). We identified a PI4K3b inhibitor-resistant RV-A16 variant with a single point mutation in the conserved 2B protein near the cytosolic carboxy terminus, isoleucine 92 to threonine (termed 2B[I92T]). The mutation did not confer resistance to cholesterol-sequestering compounds or OSBP1 inhibition, suggesting invariant dependency on the PI4P/cholesterol lipid countercurrents. In the presence of PI4K3b inhibitor, Golgi reorganization and PI4P lipid induction occurred in RV-A16 2B[I92] but not in wild-type infection. The knockout of PI4K3b abolished the replication of both the 2B[I92T] mutant and the wild type. Doxycycline-inducible expression of PI4K3b in PI4K3b knockout cells efficiently rescued the 2B[I92T] mutant and, less effectively, wild-type virus infection. Ectopic expression of 2B[I92T] or 2B was less efficient than that of 3A in recruiting PI4K3b to perinuclear membranes, suggesting a supportive rather than decisive role of 2B in recruiting PI4K3b. The data suggest that 2B tunes the recruitment of PI4K3b to the replication membrane and allows the virus to adapt to cells with low levels of PI4K3b while still maintaining the PI4P/cholesterol countercurrent for establishing Golgi-derived RV replication membranes.IMPORTANCE Human rhinoviruses (RVs) are the major cause of the common cold worldwide. They cause asthmatic exacerbations and chronic obstructive pulmonary disease. Despite recent advances, the development of antivirals and vaccines has proven difficult due to the high number and variability of RV types. The identification of critical host factors and their interactions with viral proteins and membrane lipids for the establishment of viral replication is a basis for drug development strategies. Our findings here shed new light on the interactions between nonstructural viral membrane proteins and class III phosphatidylinositol 4 kinases from the host and highlight the importance of phosphatidylinositol 4 phosphate for RV replication.

Dataset Information

Phosphatidylinositol 3-kinase, class 2 beta (PI3KC2?) isoform contributes to neuroblastoma tumorigenesis.

Publications

Phosphatidylinositol 3-kinase, class 2 beta (PI3KC2β) isoform contributes to neuroblastoma tumorigenesis.

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