PTEN Loss Antagonizes Calcitriol-Mediated Growth Inhibition in Prostate Epithelial Cells

1-alpha, 25-dihydroxy vitamin D3 (1,25(OH)2D3) elicits antiproliferative effects in a variety of cancer cell types including prostate cells while the PI3K/AKT pathway stimulates pro-survival signals. The antiproliferative effect of 1,25(OH)2D3 almost universally involves upregulation of p21 and/or p...

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Bibliographic Details
Main Author: Axanova, Linara S
Format: Report
Language:English
Subjects:
AKT INHIBITION
Biochemistry
CELLS(BIOLOGY)
MEDICAL RESEARCH
Medicine and Medical Research
MPEC(MOUSE PROSTATIC EPITHELIAL CELLS)
Pharmacology
PROSTATE CANCER
SYNERGISM
VITAMIN D
VITAMIN D3
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Summary:1-alpha, 25-dihydroxy vitamin D3 (1,25(OH)2D3) elicits antiproliferative effects in a variety of cancer cell types including prostate cells while the PI3K/AKT pathway stimulates pro-survival signals. The antiproliferative effect of 1,25(OH)2D3 almost universally involves upregulation of p21 and/or p27, while activation of PI3K/AKT downregulates p21 and p27 levels. We hypothesized that inhibition of the PI3K/AKT pathway synergizes with the antiproliferative signaling of 1,25(OH)2D3. We demonstrate that pharmacological inhibitors of PI3K or Akt restored sensitivity to antiproliferative effects of 1,25(OH)2D3 in 1,25(OH)2D3-insensitive cells and synergized to inhibit the growth of Pten-/- mouse prostatic epithelial cells, DU145, LNCaP and primary human prostate cancer cell strains. The inhibitors used included API-2 (Triciribine) and GSK690693 which are currently in clinical trials for treatment of cancer. The combination of 1,25(OH)2D3 and AKT inhibitor API-2 led to a cooperative increase in G1 arrest and in the induction of senescence. AKT is commonly activated by PTEN loss, therefore we evaluated the role of Pten in responsiveness to 1,25(OH)2D3 using shRNA knockdown and by in vitro knockout of Pten. We found that Pten status did not affect responsiveness to the antiproliferative action of 1,25(OH)2D3. These findings provide the rationale for the development of therapeutic interventions utilizing 1,25(OH)2D3 or its analogs combined with inhibition of PI3K/AKT for the treatment of prostate cancer. Includes report Axanova, et al. 1,25-dihydroxyvitamin D3 and PI3K/AKT inhibitors synergistically inhibit growth and cooperatively induce cell cycle arrest and senescence in prostate cancer cells, starting on p11. The original document contains color images. All DTIC reproductions will be in black and white.