1á,25(OH)2-VITAMIN D3 IN PROSTATE: INTERSECTION WITH AKT/PTEN AXIS AND ROLE IN SENESCENCE
type: CreativeWork
description: The PI3K-AKT pathway is frequently activated in prostate cancer and can lead to downregulation of p21 and p27 levels and function. 1-alpha, 25-dihydroxy vitamin D3 (1á,25(OH)2D3) inhibits proliferation of multiple cancer cell types, including prostate cancer cells, and upregulates p21 and/or p27. We hypothesized that inhibition of the PI3K/AKT pathway would synergize with the antiproliferative signaling of 1á,25(OH)2D3. We found that pharmacological inhibitors of PI3K or AKT and 1á,25(OH)2D3 synergistically inhibit growth of DU145, LNCaP and primary human prostate cancer cells. Combination of 1á,25(OH)2D3 and an AKT inhibitor cooperated to induce G1 arrest, senescence and higher p21 levels in prostate cancer cells. As AKT activation in prostate cancer usually occurs due to the loss of tumor suppressor PTEN, we evaluated the effect of Pten loss on 1á,25(OH)2D3)-mediated antiproliferative effects utilizing mouse prostatic epithelial cells (MPEC) with acute in vitro Pten knockdown or knockout. We found that loss of Pten expression led to a partial induction of cellular senescence. Upon treatment with 1á,25(OH)2D)3, MPEC which had lost Pten showed significantly higher levels of growth inhibition and senescence induction compared to the Pten-expressing counterparts. In contrast to the MPEC with in vitro acute deletion of Pten, Pten null MPEC isolated from Pten-deletion-driven tumors showed a complete loss of sensitivity to 1á,25(OH)2D3 -mediated growth inhibition, which was partially restored by co-treatment with a PI3K or AKT inhibitor. Moreover, this combination led to synergistic growth inhibition of tumor-derived Pten null MPEC. These observations suggest that initial loss of Pten in prostate cells may result in an increased sensitivity to 1á,25(OH)2D3-mediated antiproliferative effects, possibly by additive effect on senescence induction; whereas subsequent changes associated with tumor progression may lead to abrogation of 1á,25(OH)2D3-sensitivity, which at least p…
abstract: The PI3K-AKT pathway is frequently activated in prostate cancer and can lead to downregulation of p21 and p27 levels and function. 1-alpha, 25-dihydroxy vitamin D3 (1á,25(OH)2D3) inhibits proliferation of multiple cancer cell types, including prostate cancer cells, and upregulates p21 and/or p27. We hypothesized that inhibition of the PI3K/AKT pathway would synergize with the antiproliferative signaling of 1á,25(OH)2D3. We found that pharmacological inhibitors of PI3K or AKT and 1á,25(OH)2D3 synergistically inhibit growth of DU145, LNCaP and primary human prostate cancer cells. Combination of 1á,25(OH)2D3 and an AKT inhibitor cooperated to induce G1 arrest, senescence and higher p21 levels in prostate cancer cells. As AKT activation in prostate cancer usually occurs due to the loss of tumor suppressor PTEN, we evaluated the effect of Pten loss on 1á,25(OH)2D3)-mediated antiproliferative effects utilizing mouse prostatic epithelial cells (MPEC) with acute in vitro Pten knockdown or knockout. We found that loss of Pten expression led to a partial induction of cellular senescence. Upon treatment with 1á,25(OH)2D)3, MPEC which had lost Pten showed significantly higher levels of growth inhibition and senescence induction compared to the Pten-expressing counterparts. In contrast to the MPEC with in vitro acute deletion of Pten, Pten null MPEC isolated from Pten-deletion-driven tumors showed a complete loss of sensitivity to 1á,25(OH)2D3 -mediated growth inhibition, which was partially restored by co-treatment with a PI3K or AKT inhibitor. Moreover, this combination led to synergistic growth inhibition of tumor-derived Pten null MPEC. These observations suggest that initial loss of Pten in prostate cells may result in an increased sensitivity to 1á,25(OH)2D3-mediated antiproliferative effects, possibly by additive effect on senescence induction; whereas subsequent changes associated with tumor progression may lead to abrogation of 1á,25(OH)2D3-sensitivity, which at least p…
author: Axanova, Linara
language: en
keywords: AKT
date published: 2010
date modified: 2026-07-27T22:01:14Z
provider: Wake Forest University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Wake Forest University

PropertyValue
property ID: Handle
value: http://hdl.handle.net/10339/30431