Expression of FABP6 and FABP9 in prostate cancer and their relationship to malignant progression

The increased expression of fatty acid binding protein 4 (FABP4) and 5 (FABP5) play a crucial role in promoting tumorigenicity and metastasis of prostate cancer. FABP4 was suggested to be a therapeutic target for metastasis of prostate cancer. FABP5 was also proven to be a prognostic marker and potential treatment target. In contrast to numerous studies conducted to investigate the crucial role of FABP4 and FABP5 in prostate cancer, investigations on the possible involvement of other FABPs in the malignant progression of prostate cancer are rare. To find out whether any other FABP family proteins can also be used as diagnostic or prognostic markers for prostate cancer as FABP5, we measured the mRNA levels of 10 FABPs in benign and malignant prostate cell lines. Results showed that FABP4, FABP5, FABP6, FABP9 and FABP12 exhibited clearly higher levels in all tested malignant cell lines compared to their levels in the benign PNT-2 cells. Although, FABP4 and FABP5 have been associated with human prostate cancer as revealed in studies of our group and other groups, the finding of potential roles of FABP6, FABP9 and FABP12 have not been addressed. FABP12 is the most recently discovered member and no antibody was available for this candidate, thus FABP12 will be studied in a separate project of the group. Thereafter we assessed the expression status of FABP6 and FABP9 in both human prostate cell lines and tissues at the protein level. FABP6 protein was overexpressed only in 1 of the 5 malignant cell lines and its immunohistological staining intensities were not significantly different between the benign and the malignant prostate tissues. In contrast, FABP9 protein was highly expressed in highly malignant cell lines PC-3 and PC3-M, but its level in the benign PNT-2 and other malignant cell lines was not detectable. When analysed in an archival set of human prostate tissues, immunohistological staining intensity for FABP9 was significantly higher in carcinomas than in benign cases and the increase in FABP9 was significantly correlated with reduced patient survival times. Moreover, the increased level of staining for FABP9 was significantly associated with the increased joint Gleason scores (GS) and androgen receptor index (AR). Suppression of FABP9 expression in highly malignant PC3-M cells inhibited their invasive potential, but did not affect their growth rate, anchorage-independent growth and migration rate. Our results suggest that FABP9 is a valuable prognostic marker to predict the outcomes of prostate cancer patients, perhaps by playing an important role in prostate cancer cell invasion

Fatty acid activated PPARγ promotes tumorigenicity of prostate cancer cells by up regulating VEGF via PPAR responsive elements of the promoter.

In previous work, it is suggested that the excessive amount of fatty acids transported by FABP5 may facilitate the malignant progression of prostate cancer cells through a FABP5-PPARγ-VEGF signal transduction axis to increase angiogenesis. To further functionally characterise the FABP5-PPARγ-VEGF signal transduction pathway, we have, in this work, investigated the molecular mechanisms involved in its tumorigenicity promoting role in prostate cancer. Suppression of PPARγ in highly malignant prostate cancer cells produced a significant reduction (up to 53%) in their proliferation rate, invasiveness (up to 89%) and anchorage-independent growth (up to 94%) in vitro. Knockdown of PPARγ gene in PC3-M cells by siRNA significantly reduced the average size of tumours formed in nude mice by 99% and tumour incidence by 90%, and significantly prolonged the latent period by 3.5 fold. Results in this study combined with some previous results suggested that FABP5 promoted VEGF expression and angiogenesis through PPARγ which was activated by fatty acids transported by FABP5. Further investigations showed that PPARγ up-regulated VEGF expression through acting with the PPAR-responsive elements in the promoter region of VEGF gene in prostate cancer cells. Although androgen can modulate VEGF expression through Sp1/Sp3 binding site on VEGF promoter in androgen-dependent prostate cancer cells, this route, disappeared as the cells gradually lost their androgen dependency; was replaced by the FABP5-PPARγ-VEGF signalling pathway. These results suggested that the FABP5-PPARγ-VEGF signal transduction axis, rather than androgen modulated route, may be a more important novel therapeutic target for angiogenesis-suppression treatment of castration resistant prostate cancer