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Activation of peroxisome proliferator-activated receptor delta stimulates the proliferation of human breast and prostate cancer cell lines

Stephen, Ruth L; Gustafsson, Mattias LU ; Jarvis, Morag; Tatoud, Roger; Marshall, Barry R; Knight, Deborah; Ehrenborg, Ewa; Harris, Adrian L; Wolf, C Roland and Palmer, Colin N A (2004) In Cancer Research 64(9). p.3162-3170
Abstract
The nuclear receptor peroxisome proliferator-activated receptor delta [PPARdelta/beta (NR1C2)] has been implicated in colorectal carcinogenesis by various molecular genetic observations. These observations have recently been supported by studies of activation of PPARdelta by pharmacological agents. Here we present the first report of the stimulation of breast and prostate cancer cell growth using PPARdelta selective agonists. Activation of PPARdelta with compound F stimulated proliferation in breast (T47D, MCF7) and prostate (LNCaP, PNT1A) cell lines, which are responsive to sex hormones. Conversely, we have found that several steroid-independent cell lines, including colon lines, were unresponsive to compound F. These findings were... (More)
The nuclear receptor peroxisome proliferator-activated receptor delta [PPARdelta/beta (NR1C2)] has been implicated in colorectal carcinogenesis by various molecular genetic observations. These observations have recently been supported by studies of activation of PPARdelta by pharmacological agents. Here we present the first report of the stimulation of breast and prostate cancer cell growth using PPARdelta selective agonists. Activation of PPARdelta with compound F stimulated proliferation in breast (T47D, MCF7) and prostate (LNCaP, PNT1A) cell lines, which are responsive to sex hormones. Conversely, we have found that several steroid-independent cell lines, including colon lines, were unresponsive to compound F. These findings were confirmed with an additional high-affinity PPARdelta agonist, GW501516. Conditional expression of PPARdelta in MCF7 Tet-On cells resulted in a doxycycline-enhanced response to GW501516, thus providing direct genetic evidence for the role of PPARdelta in the proliferative response to this drug. Activation of PPARdelta in T47D cells resulted in increased expression of the proliferation marker Cdk2 and also vascular endothelial growth factor alpha (VEGFalpha) and its receptor, FLT-1, thus, suggesting that PPARdelta may initiate an autocrine loop for cellular proliferation and possibly angiogenesis. Consistent with this hypothesis, we demonstrated a pro-proliferative effect of GW501516 on human umbilical vein endothelial cell cultures and found that GW501516 also regulated the expression of VEGFalpha and FLT-1 in these cells. Our observations provide the first evidence that activation of PPARdelta can result in increased growth in breast and prostate cancer cell lines and primary endothelial cells and supports the possibility that PPARdelta antagonists may be of therapeutic value in the treatment of breast and prostate cancer. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer Research
volume
64
issue
9
pages
3162 - 3170
publisher
American Association for Cancer Research Inc.
external identifiers
  • pmid:15126355
ISSN
1538-7445
language
English
LU publication?
no
id
fc8309d4-8240-4e79-b277-c4828e76b1e0 (old id 1129938)
alternative location
http://cancerres.aacrjournals.org/content/64/9/3162.abstract
date added to LUP
2008-06-18 13:57:39
date last changed
2016-06-29 09:16:41
@article{fc8309d4-8240-4e79-b277-c4828e76b1e0,
  abstract     = {The nuclear receptor peroxisome proliferator-activated receptor delta [PPARdelta/beta (NR1C2)] has been implicated in colorectal carcinogenesis by various molecular genetic observations. These observations have recently been supported by studies of activation of PPARdelta by pharmacological agents. Here we present the first report of the stimulation of breast and prostate cancer cell growth using PPARdelta selective agonists. Activation of PPARdelta with compound F stimulated proliferation in breast (T47D, MCF7) and prostate (LNCaP, PNT1A) cell lines, which are responsive to sex hormones. Conversely, we have found that several steroid-independent cell lines, including colon lines, were unresponsive to compound F. These findings were confirmed with an additional high-affinity PPARdelta agonist, GW501516. Conditional expression of PPARdelta in MCF7 Tet-On cells resulted in a doxycycline-enhanced response to GW501516, thus providing direct genetic evidence for the role of PPARdelta in the proliferative response to this drug. Activation of PPARdelta in T47D cells resulted in increased expression of the proliferation marker Cdk2 and also vascular endothelial growth factor alpha (VEGFalpha) and its receptor, FLT-1, thus, suggesting that PPARdelta may initiate an autocrine loop for cellular proliferation and possibly angiogenesis. Consistent with this hypothesis, we demonstrated a pro-proliferative effect of GW501516 on human umbilical vein endothelial cell cultures and found that GW501516 also regulated the expression of VEGFalpha and FLT-1 in these cells. Our observations provide the first evidence that activation of PPARdelta can result in increased growth in breast and prostate cancer cell lines and primary endothelial cells and supports the possibility that PPARdelta antagonists may be of therapeutic value in the treatment of breast and prostate cancer.},
  author       = {Stephen, Ruth L and Gustafsson, Mattias and Jarvis, Morag and Tatoud, Roger and Marshall, Barry R and Knight, Deborah and Ehrenborg, Ewa and Harris, Adrian L and Wolf, C Roland and Palmer, Colin N A},
  issn         = {1538-7445},
  language     = {eng},
  number       = {9},
  pages        = {3162--3170},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {Activation of peroxisome proliferator-activated receptor delta stimulates the proliferation of human breast and prostate cancer cell lines},
  volume       = {64},
  year         = {2004},
}