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Title: Molecular mechanisms of the apoptosis-promoting activity of FABP5 inhibitors in prostate cancer cells
Author: Zhang, Jiacheng
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2019
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The increased level of FABP5 promotes tumourigenicity and metastasis partially by suppressing apoptosis of prostate cancer cells. Recent studies demonstrated that in castration-resistant prostate cancer cells, androgen-receptor related signaling pathway did not effectively affect the malignant progression, whereas FABP5-PPARγ-VEGF signaling axis had a dominant influence in promoting the malignant progression. Therefore, targeting FABP5 with its inhibitors to promote apoptosis could be a novel strategy for prostate cancer treatment. In this work, we first treated an androgen-responsive cell line 22Rv1 and a highly malignant androgen-independent cell line PC3 with a chemically synthesized FABP5 inhibitor SB-FI-26 and a bioFABP5-inhibitor dmrFABP5, respectively, to prove their promoting effect on apoptosis of the cancer cells; then we investigated the molecular mechanisms involved in how FABP5 inhibitor promoted apoptosis. Results showed that SB-FI-26 produced significant increases in percentages of apoptotic cells in both 22Rv1 and PC3 by 18.80% (±4.08) and 4.60% (±1.13), respectively. DmrFABP5 produced significant increases in percentages of apoptotic cells by 23.13% (±2.41) and 15.76% (±3.01), respectively, in these two cell lines. Both FABP5 inhibitors significantly reduced the levels of the phosphorylated (presumably, biologically active form) nuclear fatty acid receptor PPARγ, indicating that these inhibitors promoted apoptosis of the cancer cells through suppressing the biological activity of PPARγ. Further studies showed that, as the reduction of the level of p-PPARγ, the levels of AKT and NFκB were coordinately altered. These changes eventually led to the increased levels of cleaved Caspase-9 and cleaved Caspase-3 and thus increased number of apoptotic cells. These results, together with some previous studies, suggested that FABP5 inhibitors promoted apoptosis in prostate cancer cells by suppressing the biological effect of FABP5, and FBAP5 may suppress apoptosis through increasing the biological activity of PPARγ, which, in turn, leads to a reduced apoptosis by interfering with the AKT and NFκB signaling pathway.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral