Decreased expression and androgen regulation of the tumor suppressor gene INPP4B in prostate cancer

Cancer Res. 2011 Jan 15;71(2):572-82. doi: 10.1158/0008-5472.CAN-10-2314. Epub 2011 Jan 11.


Patients with metastatic prostate cancer who undergo androgen-ablation therapy invariably relapse and develop incurable castration-resistant disease. Activation of the prosurvival Akt pathway accompanies androgen ablation. We discovered that the androgen receptor induces the expression of the tumor suppressor inositol polyphosphate 4-phosphatase type II (INPP4B) but not PTEN in prostate cancer cells. Optimal induction of INPP4B by an androgen receptor required the expression of the transcriptional coactivator NCoR. INPP4B dephosphorylates phosphatidylinositol-3, 4-bisphosphate, which leads to reduced phosphorylation and activity of Akt. In support of a key role for INPP4B in Akt control, INPP4B depletion activated Akt and increased cellular proliferation. The clinical significance of INPP4B in androgen-dependent prostate cancers was determined in normal or primary tumor prostate tissues derived from radical prostatectomy specimens. In primary tumors, the expression of both INPP4B and PTEN was substantially reduced compared with normal tissue. Further, the decreased expression of INPP4B reduced the time to biochemical recurrence. Thus, androgen ablation can activate the Akt pathway via INPP4B downregulation, thereby mitigating the antitumor effects of androgen ablation. Our findings reinforce the concept that patients undergoing androgen ablation may benefit from Akt-targeting therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgens / metabolism
  • Androgens / pharmacology*
  • Cell Growth Processes / physiology
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor*
  • Humans
  • Male
  • Neoplasm Recurrence, Local / enzymology
  • Neoplasm Recurrence, Local / metabolism
  • PTEN Phosphohydrolase / biosynthesis
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Phosphoric Monoester Hydrolases / biosynthesis
  • Phosphoric Monoester Hydrolases / deficiency
  • Phosphoric Monoester Hydrolases / genetics*
  • Prostatic Neoplasms / enzymology*
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Androgen / genetics
  • Transfection


  • Androgens
  • Receptors, Androgen
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • phosphatidylinositol-3,4-bisphosphate 4-phosphatase
  • PTEN Phosphohydrolase
  • PTEN protein, human