Identification of a C-FABP-PPARγ-VEGF axis promoting tumorigenicity in prostate cancer cells



Seyed Forootan, Farzad
Identification of a C-FABP-PPARγ-VEGF axis promoting tumorigenicity in prostate cancer cells. PhD thesis, University of Liverpool.

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Abstract

The over-expression of C-FABP plays an important role in promoting tumorigenicity of prostate cancer. It has been hypothesized that the overexpressed C-FABP may transport an excessive amount of intracellular fatty acids into cancer cells to activate their nuclear receptor PPARγ to trigger a chain of molecular events that may lead to a facilitated malignant progression of the cancer cells. To investigate whether PPARγ involved in activities exerted by C-FABP in prostate cancer, their expression status was assessed in prostate cell lines and tissues. Results showed that their expression levels in malignant cell lines and tissues (cytoplasm and nucleus) were significantly higher than those expressed in benign cells and in BPH and it appeared that their expression levels were increased as the increasing malignancies of the cell lines and tissues. The increased expression of both C-FABP and PPARγ were significantly correlated to a reduced survival time. Suppression of PPARγ in highly malignant prostate cancer cells produced a significant reduction in growth rate (up to 53%), invasiveness (up to 89%) and anchorage-independent growth (up to 94%) in vitro. Suppression of PPARγ in PC3-M cells could significantly reduce the sizes of tumours formed in nude mice by 99%. Tumour incidence was reduced to 10% and the latent period was significantly increased by 3.5 fold. The results in this study also showed that C-FABP promoted VEGF expression and angiogenesis by PPARγ (through the stimulation of the fatty acids transported by C-FABP). When PPARγ was blocked with its antagonists, cells did not respond to stimulation signal produced by fatty acids, even when high level of fatty acids was available. Further study showed that the activated PPARγ regulated VEGF expression through acting with the PPREs in the promoter region of VEGF in prostate cancer. Although androgen can modulate VEGF expression through Sp1/Sp3 binding site on VEGF promoter in androgen-dependent prostate cancer cells, this route was disappeared and gradually replcaced by the C-FABP-PPARγ route as the cells gradually lost their androgen dependency. The results of this study suggested that C-FABP, together with fatty acids, PPARγ and VEGF should be considered as key factors in the fatty acids-initiated signalling pathway that promoted the malignant progression. Therefore, the C-FABP-PPARγ-VEGF axis may be a novel therapeutic target for prostatic cancer.

Item Type: Thesis (PhD)
Additional Information: Date: 2014-07 (completed)
Depositing User: Symplectic Admin
Date Deposited: 19 Feb 2015 14:02
Last Modified: 17 Dec 2022 01:30
DOI: 10.17638/02003526
URI: https://livrepository.liverpool.ac.uk/id/eprint/2003526