Visit our Expo - Redox and Inflammation signaling 2012

Session XVII : Cell signaling in health and disease Poster XVII, 10
Androgens induce while PPAR-ligands inhibit prostate cancer cells migration.
Joanna Duli"ska-Litewka, Dorota Gil and Piotr Laidler
Department of Medical Biochemistry, Jagiellonian University Medical College, ul.
Kopernika 7, 31-034 Kraków, POLAND; e-mail: mblitewk@kinga.cyf-kr.edu.pl,
tel/fax:+48(12)4223272
Purpose: Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes which
degrade the extracellular matrix or components of the basement membrane. MMP have been
found to be associated with prostate cancer metastasis. Prostate growth, survival and
pathology is generally dependent on androgen stimulation mediated by the androgen receptor
(AR). Several ligands of peroxisome proliferators activated receptors (PPARs) were shown to
decrease the proliferation and enhance apoptosis in various cancers, also in prostate cancer
thus somehow opposing androgen effects. Therefore we sought to determine if and how
androgens and PPAR-ligands influence MMPs expression and prostate cancer cells migration.
Methods: Studies were carried out on human prostate cancer cell lines: LNCaP, Du-145 and
PC-3. We studied the effect of testosterone and PPAR$ ligands (ciglitazone, arachidonic acid)
on cells’ migration (Boyden’s chamber), expression and activity of MMPs (zymography) and
selected proteins engaged in cell signaling (RT-PCR, Western blot). The antagonist of PPAR$
– GW9662 and inhibitor of 5"-reductase – finasteride were also included.
Results: Treatment of LNCaP cells with testosterone resulted in an increase of pro-MMP-2
expression and MMP-2 activity and led to the increased proliferation and decreased
expression of PPAR$. Finasteride clearly suppressed this effects. Selective PPAR$ ligands
significantly decreased proliferation, migration and the level of active MMPs. RT-PCR and
Western blot analyses basically indicated the opposite effects of testosterone and ciglitazone
on expression of AR, PPAR$, c-myc and Akt. Inhibition of the expression of phosphorylated
Akt by ciglitazone did not affect total Akt levels, indicating the functional effect of PPAR$
ligand on Akt signal transduction.
Conclusions: The results suggest that the expression and regulation of the activity of AR and
PPAR$ significantly and clearly in opposite manner affect prostate cancer cell proliferation,
migration and MMP expression. It seems that important signaling step in androgen-induced
migration might be inhibited by PPAR$ ligands. Moreover, Akt signal transduction seems to
be linked to AR and PPAR ligands modulation of these basic cell properties through as yet
not fully recognized mechanism. This results may provide a novel target of PPAR$ activators
and indicate their potential as useful therapeutic agents in the treatment of prostate cancer.
This work was financially supported by the KBN: Jagiellonian University Medical College –
grant W,/253/P/L and the State Committee for Scientific Research - grant No 6 PO5A 074 21,
Poland
- 617 -