Evidence that Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor that Inhibits PI3K Signaling

被引：456

作者：

Gewinner, Christina ^{[1
]}

Wang, Zhigang C. ^{[3
]}

Richardson, Andrea ^{[3
]}

Teruya-Feldstein, Julie ^{[4
]}

Etemadmoghadam, Dariush ^{[5
]}

Bowtell, David ^{[5
]}

Barretina, Jordi ^{[6
]}

Lin, William M. ^{[6
]}

Rameh, Lucia ^{[7
]}

Salmena, Leonardo ^{[2
]}

Pandolfi, Pier Paolo ^{[2
]}

Cantley, Lewis C. ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Signal Transduct,Dept Syst Biol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Beth Israel Deaconess Canc Ctr, Canc Genet Program, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[4] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[5] Peter MacCallum Canc Ctr, Melbourne, Vic 8006, Australia

[6] Broad Inst, Cambridge, MA 02142 USA

[7] Boston Biomed Res Inst, Watertown, MA 02472 USA

来源：

CANCER CELL | 2009年 / 16卷 / 02期

关键词：

PROTEIN-KINASE-B; PHOSPHOINOSITIDE 3-KINASE PATHWAY; COMPARATIVE GENOMIC HYBRIDIZATION; ONCOGENE-INDUCED SENESCENCE; PLECKSTRIN HOMOLOGY DOMAIN; DNA COPY NUMBER; BREAST-CANCER; PHOSPHATIDYLINOSITOL; 3-KINASE; PTEN; CELLS;

D O I：

10.1016/j.ccr.2009.06.006

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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)P-2) with no effect on phosphatidylinositol-3.4.5-triphosphate (PI(3,4,5)P-3), suggesting that PI(3,4)P-2 and PI(3,4,5)P-3 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.

引用

页码：115 / 125

页数：11

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