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. 2019 Sep 16;9(1):13284.
doi: 10.1038/s41598-019-49486-2.

Fatty Acid Inhibition Sensitizes Androgen-Dependent and -Independent Prostate Cancer to Radiotherapy via FASN/NF-κB Pathway

Hui-Yen Chuang  1 , Yen-Po Lee  1 , Wei-Chan Lin  1   2   3 , Yi-Hsien Lin  4   5 , Jeng-Jong Hwang  6   7
Affiliations

Fatty Acid Inhibition Sensitizes Androgen-Dependent and -Independent Prostate Cancer to Radiotherapy via FASN/NF-κB Pathway

Hui-Yen Chuang et al. Sci Rep. .

Abstract

Elevated fatty acid synthase (FASN) has been reported in both androgen-dependent and -independent prostate cancers. Conventional treatment for prostate cancer is radiotherapy (RT); however, the following radiation-induced radioresistance often causes treatment failure. Upstream proteins of FASN such as Akt and NF-κB are found increased in the radioresistant prostate cancer cells. Nevertheless, whether inhibition of FASN could improve RT outcomes and reverse radiosensitivity of prostate cancer cells is still unknown. Here, we hypothesised that orlistat, a FASN inhibitor, could improve RT outcomes in prostate cancer. Orlistat treatment significantly reduced the S phase population in both androgen-dependent and -independent prostate cancer cells. Combination of orlistat and RT significantly decreased NF-κB activity and related downstream proteins in both prostate cancer cells. Combination effect of orlistat and RT was further investigated in both LNCaP and PC3 tumour-bearing mice. Combination treatment showed the best tumour inhibition compared to that of orlistat alone or RT alone. These results suggest that prostate cancer treated by conventional RT could be improved by orlistat via inhibition of FASN.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Orlistat suppressed proliferation and caused cell cycle changes in LNCaP and PC3 cells. Orlistat resulted in significant G1 phase accumulations and S and G2/M phase reductions in both (C) LNCaP and (D) PC3 cells in a dose-dependent manner. Moreover, orlistat also caused increases in the sub-G1 population in LNCaP cells but not in PC3 cells. (a, p < 0.05 compared with 0 μM; b, p < 0.05 compared with 15 μM; c, p < 0.05 compared with 30 μM; d, p < 0.05 compared with 60 μM; e, p < 0.05 compared with 20 μM; f, p < 0.05 compared with 40 μM).
Figure 2
Figure 2
Radiation survival curves of LNCaP and PC3 cells. Radiation surviving curves of (A) LNCaP and (B) PC3 cells were built based on the colony formation results, and the D1 of both cell lines are calculated. The D1 values of LNCaP and PC3 cells were 1.1 Gy and 2 Gy, respectively. The D1 of both cell lines were used in the following combination treatments.
Figure 3
Figure 3
Orlistat alters the protein expression profiles and the NF-κB activity in LNCaP and PC3 cells. The protein expressions were evaluated by Western blotting. (A,B) Orlistat reduced the expressions of FASN, pAkt, VEGF, cyclin D1, and Bcl-2 in both cell lines. Additionally, slightly increased cleaved caspase-3 was also detected. Decreased androgen receptor (AR) and elevated p-p53/p53 levels were found in LNCaP cells after orlistat treatment. (C,D) NF-κB activity was determined by the EMSA assay, and orlistat inhibited the NF-κB activity in both cell lines in a dose-dependent manner. PC3 cells showed a more profound reduction in NF-κB activity at the dose of IC50 than LNCaP cells. (a, p < 0.05 compared with 0 μM; b, p < 0.05 compared with 15 μM; c, p < 0.05 compared with 30 μM).
Figure 4
Figure 4
NF-κB activity change was determined by EMSA assay, and the changes in protein expression profiles were detected by Western blotting. Lower NF-κB activities were found in orlistat and RT-treated (A) LNCaP and (B) PC3 cells. The lowest NF-κB activity among all the combination groups was detected in the concurrent group and pretreated group in LNCaP and PC3, respectively. According to the EMSA findings, LNCaP and PC3 cells were received concurrent and pretreatment for the subsequent Western blotting. (C) RT slightly reduced FASN, AR, and cyclin D1 expressions in LNCaP cells and these reductions were further enhanced by the combination treatment. Also, combination treatment increases p53 and p-p53. (D) Similar effects on protein expression changes were also observed in PC3 cells except for AR, p53, and p-p53, which are not expressed by PC3 cells.
Figure 5
Figure 5
Orlistat synergistically improves RT outcomes in both LNCaP and PC3 tumor-bearing mice. The combination treatment significantly suppressed (A) LNCaP and (B) PC3 tumor growth. Significant differences in tumor sizes were found between COMB, ORL, and RT groups as indicated in the figure. (a, p < 0.05 compared with Control; b, p < 0.05 compared with orlistat; c, p < 0.05 compared with RT).
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