PTEN Loss Antagonizes Calcitriol-mediated Growth Inhibition in Prostate Epithelial Cells
Annual summary rept. 21 Apr 2009-20 Apr 2010
WAKE FOREST UNIV WINSTON-SALEM NC SCHOOL OF HEALTH SCIENCES
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1-alpha, 25-dihydroxy vitamin Dsub 3 1,25OH2D3 inhibits proliferation of multiple cancer cell types including prostate cells and upregulates p21 andor p27, while loss of Pten and PI3KAKT activation stimulates survival and downregulates p21 and p27. We hypothesized that inhibition of the PI3KAKT pathway synergizes with the antiproliferative signaling of 1,25OHsub 2Dsub 3. Viability, cell cycle and senescence of cells were evaluated upon combinational treatment with 1,25OHsub 2Dsub 3 and pharmacological PI3KAKT inhibitors. Pharmacological inhibitors of PI3K or Akt and 1,25OHsub 2Dsub 3 synergistically inhibited growth of DU145, LNCaP, primary human prostate cancer cell strains and Pten null mouse prostatic epithelial cells MPEC. The inhibitors used included API-2 Triciribine and GSK690693 which are currently in clinical trials for treatment of cancer. A novel mechanism for antiproliferative effects of 1,25OHsub 2Dsub 3 in prostate cells, induction of senescence, was discovered. Combination of 1,25OHsub 2Dsub 3 and AKT inhibitor cooperated to induce G1 arrest, senescence, and p21 levels in prostate cancer cells. As AKT is commonly activated by PTEN loss, we evaluated the role of Pten in responsiveness to 1,25OHsub 2Dsub 3 using shRNA knockdown and by in vitro knockout of Pten. MPEC that lost Pten expression remained sensitive to the antiproliferative action of 1,25OHsub 2Dsub 3, and showed higher degree of synergism between AKT inhibitor and 1,25OHsub 2Dsub 3 compared to Pten-expressing counterparts. CONCLUSIONS These findings provide the rationale for the development of therapies utilizing 1,25OHsub 2Dsub 3 or its analogs combined with inhibition of PI3KAKT for the treatment of prostate cancer.
- Medicine and Medical Research