Abstract
Previous study has suggested that the FABP5-PPARγ-signalling transduction pathway gradually replaces the androgen receptor activated pathway in promoting malignant progression of castration-resistant prostate cancer (CRPC) cells. To interfere with this newly discovered FABP5-related signalling pathway, we have produced a highly efficient recombinant FABP5 inhibitor, named dmrFABP5. Treatment with dmrFABP5 significantly supressed the proliferation, migration, invasion and colony formation of the highly malignant prostate cancer cells PC3-M in vitro. To test dmrFABP5's suppressive effect in CRPC, the human PC3-M cells were implanted orthotopically into the prostate gland of immunosuppressed mice to produce tumours. These mice were then treated with dmrFABP5 and produced a highly significant reduction of 100% in metastatic rate and a highly significant reduction of 13-fold in the average size of primary tumours. Immunocytochemial staining showed that the staining intensity of dmrFABP5 treated tumours was reduced by 67%. When tested in vitro, dmrFABP5 suppressed the cancer cells by blocking fatty acid stimulation of PPARγ, and thereby prevented it activating down-stream cancer-promoting or inhibiting cancer-suppressing genes. Our results show that the FABP5 inhibitor dmrFABP5 is a novel molecule for treatment of experimental CRPC and its inhibitory effect is much greater than that produced by SB-FI-26 reported in our previous work.
Highlights
Prostate cancer is common in countries with a high dietary consumption of fatty acids [1]
When palmitic acid was added to complexes of dmrFABP5 + B +D, the level of fluorescent intensity was only slightly reduced by 7%, indicating that dmrFABP5 was able to replace only 7% of the DAUDA, dmrFABP5 had lost most of its ability of binding to fatty acids
The main theory to date is that the biological sensitivity of androgen receptor (AR) is selectively amplified after the first round of Androgen-deprivation therapy (ADT) to such an extent that even micro-quantities of the remaining male hormone in peripheral blood can still promote the malignant progression of castration-resistant prostate cancer (CRPC) cells [29]
Summary
Prostate cancer is common in countries with a high dietary consumption of fatty acids [1]. In most cases the disease relapses within 2–3 years with recurrence of lethal castration-resistant prostate cancer (CRPC). This disease cannot be treated effectively by ADT [2]. Fatty acids are active components of many biological processes, and are essential signal transduction molecules in pathways involved in advanced prostate cancer progression [6,7,8]. Recent investigations have established that there is a novel fatty acid-initiated signalling pathway that leads to malignant progression of prostatic cancer cells. When FABP5 expression is increased, excessive amounts of fatty acids are transported into the nucleus of the prostate cancer cells, where they act as signalling molecules to stimulate their nuclear receptor PPARγ. The activated PPARγ modulates the expression of its down-stream regulatory genes and these changes lead to enhanced tumour expansion and aggressiveness caused by an overgrowth of cells with increased angiogenesis and reduced apoptosis [16]
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