Journal
CELL BIOLOGY INTERNATIONAL
Volume 47, Issue 5, Pages 929-942Publisher
WILEY
DOI: 10.1002/cbin.11989
Keywords
AB-FI-26; apoptosis; dmrFABP5; FABP5; PPAR gamma; prostate cancer
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Previous work showed that FABP5 inhibitors suppress the malignant progression of prostate cancer cells by promoting apoptosis. This study further investigated the mechanisms involved and found that the inhibitors reduce the activity of PPAR gamma and alter the AKT and NF kappa B signaling pathways, leading to increased apoptosis in cancer cells.
Previous work showed that FABP5 inhibitors suppressed the malignant progression of prostate cancer cells, and this suppression might be achieved partially by promoting apoptosis. But the mechanisms involved were not known. Here, we investigated the effect of inhibitors on apoptosis and studied the relevant mechanisms. WtrFABP5 significantly reduced apoptotic cells in 22Rv1 and PC3 by 18% and 42%, respectively. In contrast, the chemical inhibitor SB-FI-26 produced significant increases in percentages of apoptotic cells in 22Rv1 and PC3 by 18.8% (+/- 4. 1) and 4.6% (+/- 1.1 ), respectively. The bio-inhibitor dmrFABP5 also did so by 23.1% (+/- 2.4 ) and 15.8% (+/- 3.0), respectively, in these cell lines. Both FABP5 inhibitors significantly reduced the levels of the phosphorylated nuclear fatty acid receptor PPAR gamma, indicating that these inhibitors promoted apoptosis-induct ion sensitivity of the cancer cells by suppressing the biological activity of PPAR gamma. Thus, the phosphorylated PPAR gamma levels were reduced by FABP5 inhibitors, the levels of the phosphorylated AKT and activated nuclear factor kapper B (NF kappa B) were coordinately altered by additions of the inhibitors. These changes eventually led to the increased levels of cleaved caspase-9 and cleaved caspase-3; and thus, increase in the percentage of cells undergoing apoptosis. In untreated prostate cancer cells, increased FABP5 suppressed the apoptosis by increasing the biological activity of PPAR gamma, which, in turn, led to a reduced apoptosis by interfering with the AKT or NF kappa B signaling pathway. Our results suggested that the FABP5 inhibitors enhanced the apoptosis-induct ion of prostate cancer cells by reversing the biological effect of FABP5 and its related pathway.
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