A237: Suppressing tumorigenicity of prostate cancer by FABP5 inhibitors

Waseem Al-Jameel1,Shiva Forootan1,Syed Hussain1,Philip Cornford1,Youqiang Ke1

1Uinversity of Liverpool, Liverpool, UK

Presenting date: Monday 2 November
Presenting time: 12.20-13.10

Background

 Fatty Acid- Binding Protein 5 (FABP5) is a tumourigenicity promoter overexpressed in prostatic cancer cells. It was suggested that the biological activity of FABP5 to stimulate tumourigencity of prostate cancer cells depends on its ability of binding and transporting fatty acids which act as signalling molecules to motivate their nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR?). The activated PPAR? may then regulate the down-stream cancer-related genes to facilitate the malignant progression. Our previous work showed that nearly complete inhibition of tumourigenicity of prostate cancer cells can be achieved through suppressing the expression of FABP5 by RNAi. But RNAi molecules cannot be used as drugs directly due to their instability. In this study, we are aimed to establish experimental therapeutics on advanced prostate cancer by using a bio-reagent FABP5 inhibitor (A) and a chemically synthesized inhibitor (B) to inhibit the tumourigenicity of prostate cancer cells through effectively suppressing FABP5 activity.

Method

 The effect of inhibitor A and B on the biological activity of FABP5 was first tested by Fluorescence Displacement DAUDA Assay to assess their ability to suppress the binding between FABP5 and the extracellular or intracellular fatty acids; then tested by fatty acid uptake assay to assess their ability to inhibit the cellular fatty acid uptake. The inhibitory effect of inhibitor A and B on the proliferation, immigration, invasiveness and tumourigenicity of prostate cancer cells were tested bioassays in vitro and then in nude mouse.

Results

 Our work showed that inhibitor A can effectively prevent the fatty acids to activate PPAR?. Inhibitor B can almost completely deprive of the ability of FABP5 to bind to the fatty acids. The results showed that both inhibitor A and B significantly reduced the cancer cell proliferation (by 25% and 40%), immigration (by 80%), invasiveness (by 90%) and colony formation ability in soft agar (by 75%). The nude mouse assay results showed that in comparison with the control, both inhibitors A (by 70%) and B (by 58%) produced significant reductions in average tumour sizes (Student t-test; p<0.0001, P<0.001). The average volumes (210mm3 in A Group; 287mm3 in B group) of tumours produced by the groups of mice treated with inhibitors were significantly lower than that produced by the control group (688 mm3). The reduction in average tumour sizes produced by inhibitor A is significantly higher (by 37%) than that produced by inhibitor B (Student t-test p < 0.05).

Conclusion

 Both FABP5 inhibitors used in this study can effectively suppress tumorigenicity of the highly malignant prostatic cancer cells; inhibitor A is at least 37% more efficient than inhibitor B.