TY - JOUR
T1 - Evidence that Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor that Inhibits PI3K Signaling
AU - Gewinner, Christina
AU - Wang, Zhigang C.
AU - Richardson, Andrea
AU - Teruya-Feldstein, Julie
AU - Etemadmoghadam, Dariush
AU - Bowtell, David
AU - Barretina, Jordi
AU - Lin, William M.
AU - Rameh, Lucia
AU - Salmena, Leonardo
AU - Pandolfi, Pier Paolo
AU - Cantley, Lewis C.
PY - 2009/8/4
Y1 - 2009/8/4
N2 - We report that knocking down the expression of inositol polyphosphate 4-phosphatase type II (INPP4B) in human epithelial cells, like knockdown of PTEN, resulted in enhanced Akt activation and anchorage-independent growth and enhanced overall motility. In xenograft experiments, overexpression of INPP4B resulted in reduced tumor growth. INPP4B preferentially hydrolyzes phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) with no effect on phosphatidylinositol-3.4.5-triphosphate (PI(3,4,5)P3), suggesting that PI(3,4)P2 and PI(3,4,5)P3 may cooperate in Akt activation and cell transformation. Dual knockdown of INPP4B and PTEN resulted in cellular senescence. Finally, we found loss of heterozygosity (LOH) at the INPP4B locus in a majority of basal-like breast cancers, as well as in a significant fraction of ovarian cancers, which correlated with lower overall patient survival, suggesting that INPP4B is a tumor suppressor.
AB - We report that knocking down the expression of inositol polyphosphate 4-phosphatase type II (INPP4B) in human epithelial cells, like knockdown of PTEN, resulted in enhanced Akt activation and anchorage-independent growth and enhanced overall motility. In xenograft experiments, overexpression of INPP4B resulted in reduced tumor growth. INPP4B preferentially hydrolyzes phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) with no effect on phosphatidylinositol-3.4.5-triphosphate (PI(3,4,5)P3), suggesting that PI(3,4)P2 and PI(3,4,5)P3 may cooperate in Akt activation and cell transformation. Dual knockdown of INPP4B and PTEN resulted in cellular senescence. Finally, we found loss of heterozygosity (LOH) at the INPP4B locus in a majority of basal-like breast cancers, as well as in a significant fraction of ovarian cancers, which correlated with lower overall patient survival, suggesting that INPP4B is a tumor suppressor.
KW - CELLCYCLE
UR - http://www.scopus.com/inward/record.url?scp=67651148274&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67651148274&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2009.06.006
DO - 10.1016/j.ccr.2009.06.006
M3 - Article
C2 - 19647222
AN - SCOPUS:67651148274
SN - 1535-6108
VL - 16
SP - 115
EP - 125
JO - Cancer Cell
JF - Cancer Cell
IS - 2
ER -