Investigation of the promoting roles of FABP5 and AR in malignant progression of prostate cancer cells and the relevant molecular mechanisms

Abstract

FABP5 and the androgen receptor (AR) are two important promoting factors for the malignant progression of prostate cancer cells. To study the molecular mechanisms underlying their tumor-promoting function, we first knocked out FABP5 or AR in the moderately malignant 22RV1 cells and in the highly malignant DU145 and PC3M cells, respectively. Then we investigated the effect of FABP5- or AR- knock out (KO) on the malignant characteristics of the cancer cells and detected the changes in expression status of the main factors involved the FABP5 or AR-PPARγ-VEGF signal pathway. To investigate the complexed signal network regulated by FABP5 and AR, we compared the expression profiles between the parental cells and the FABP5- or AR- KO cells. Our results showed that FABP5- or AR- KO significantly suppressed the cell proliferation rate, invasive ability, motility rate, and anchorage-independent growth through disrupting the FABP5 or AR-p-PPARγ-VEGF axis. It was found that FABP5 and AR interacted with each other in regulation of FABP5 or AR - p-PPARγ-VEGF axis, with FABP5 controlling the ARV7 splice variant and AR regulating the expression of FABP5. RNA profile comparison led to the identification of a large number of differentially expressed genes (DEG) between the parental and FABP5- or AR- KO cells. Six most pronouns DEGs were shown to be involved in the transition of the cells from androgen-responsive to androgen-unresponsive prostate cancer or CRPC cells. Gene ontology enrichment analysis revealed that the top enriched biological processes of DEGs included those response to fatty acids, cholesterol, and sterol biosynthesis, as well as lipid and fatty acid transport. These pathways regulated by FABP5 or AR were crucial in transducing signals for cancer cell progression. Our results suggested that the interactions between FABP5 and AR contributed to the transition of prostate cancer cells to the androgen-independent state.