National Cancer Research Institute South of England
Prostate Cancer Collaborative
Research

 

Targeting peroxisome proliferation activator receptors (PPARs) in prostate carcinoma

Author

Dr Christopher Bunce

University of Birmingham

Dr Bunce has been studying the biology of an enzyme known as AKR1C3. (Figure 1) In particular he has been studying how inhibitors of this enzyme which include certain steroids and also non-steroidal anti-inflammatory drugs, exert anti-tumour effects against human leukaemia cells. Based on his studies he and other researchers in Birmingham have begun clinical trials aimed at exploiting this new tumour target in acute myeloid leukaemia.

Fig1

As in leukaemia cells, AKR1C3 is also expressed in prostate cancer cells. Dr Bunce approached us to fund pilot studies that would help determine whether similar strategies could be of benefit in the treatment/management of prostate cancer. He has teamed up with Dr Moray Campbell who is another Birmingham based researcher and has had a long track record in studies of prostate cancer. Consequently the project is supported by complementary sets of expertise and backgrounds.

Dr Bunce has two basic questions that he wishes his and Dr Campbell's studies to address. First they wish to determine whether modulation of AKR1C3 activity in prostate cancer cells changes their survival/proliferation or indeed their sensitivities to signals for differentiation. This question will be approached using AKR1C3 inhibitors and also using molecular approaches to remove or reduce

AKR1C3 expression. On the other hand Dr Campbell and Dr Bunce will test whether increasing the level of AKR1C3 expression reciprocally effects proliferation, survival and differentiation.

The second question will address the question of how AKR1C3 regulates prostate cancer cell behaviour. Other workers in the field have suggested that the importance of ALKR1C3 expression in the prostate is related to its ability to metabolise androgens. It has therefore been proposed as a key regulator of signalling via the androgen nuclear hormone receptor (AR) in prostate cells. If true this is clearly very important. However Dr Bunce first discovered the anti-tumour effect of AKR1C3 inhibitors in androgen receptor negative HL-60 leukaemia cells. He also noted that treatment of HL-60 cells with neither androgen AKR1C3 substrates or products altered the neoplastic biology of the cells. He therefore reasoned that a separate substrate must be important. This second substrate turned out to be a prostaglandin not a steroid substrate. AKR1C3 has prostaglandin D2 11-ketoreductase activity and therefore works to deplete PGD2 in cells. Whereas adding androgen AKR1C3 substrates to HL-60 cells had little effect, addition of excess PGD2 mimicked the action of AKR1C3 inhibition.

PGD2 is an unstable prostanoid and converts rapidly J-series prostaglandins that act as activating ligands of the PPARgamma nuclear receptor. (Figure 2)

Fig2

Dr Bunce has therefore proposed that the importance of AKR1C3 in leukemia cells is in regulating PPARgamma and not AR. This therefore raises the question whether AKR1C3 in prostate cells also regulates PPARgamma and not AR or alternatively either AR alone or both receptors. The studies to be undertaken by Drs Bunce and Campbell will address these questions.   

 
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Contact us on Email: cbell@icr.ac.uk Tel: 0208 643 8901 Fax: 0208 770 7290 This page last modified: 3/12/04