The intriguing role of fibroblasts and c-Jun in the chemopreventive and therapeutic effect of finasteride on xenograft models of prostate cancer

Abstract

In a large clinical trial, finasteride reduced the rate of low-grade prostate cancer (PCa) while increasing the incidence of high-grade cancer. Whether finasteride promotes the development of high-grade tumors remains controversial. We demonstrated the role of fibroblasts and c-Jun in chemopreventive and therapeutic effect of finasteride on xenograft models of PCa. LNCaP (PC3) cells or recombinants of cancer cells and fibroblasts were implanted in male athymic nude mice treated with finasteride. Tumor growth, cell proliferation, apoptosis, p-Akt, and p-ERK1/2 were evaluated. In LNCaP (PC3) mono-grafted models, finasteride did not change the tumor growth. In recombinant-grafted models, fibroblasts and c-Jun promoted tumor growth; finasteride induced proliferation of LNCaP cells and repressed PC3 cell apoptosis. When c-Jun was knocked out, fibroblasts and/or finasteride did not promote the tumor growth. Finasteride inhibited p-Akt and p-ERK1/2 in mono-culture cancer cells while stimulating the same signaling molecules in the presence of fibroblasts. Reduced p-Akt and p-ERK1/2 were noted in the presence of c-Jun-/- fibroblasts. Fibroblasts and c-Jun promote PCa growth; finasteride further stimulates tumor growth with promoted proliferation, repressed apoptosis, and up-regulated pro-proliferative molecular pathway in the presence of fibroblasts and c-Jun. Stromal-epithelial interactions play critical roles in finasteride's therapeutic effects on PCa. Our findings have preliminary implications in using finasteride as a chemopreventive or therapeutic agent for PCa patients.

Figure 1

The growth curves of the LNCaP (a) and PC3 (b) mono-grafted and cancer cell-fibroblast recombinant-grafted tumors in the xenograft PCa mouse model. Finasteride did not change the tumor growth of LNCaP or PC3 mono-grafted tumors or in the presence of fibroblasts.

Figure 2

Comparisons of the final tumor volumes and weights after grafted tumors were removed from mice. (a) and (b) Compared the LNCaP tumor volumes and weights among groups on the 50^th day from implantation of tumor cells. Finasteride stimulated the LNCaP tumor growth in the presence of wild fibroblasts. (c) and (d) Compared the PC3 tumor volumes and weights among groups on the 43^th day from implantation of tumor cells. Finasteride stimulated the PC3 tumor growth in the presence of wild fibroblasts. c-Jun is important in mediating the pro-proliferative effects of fibroblasts and Finasteride for both LNCaP and PC3 grafted tumors.

Figure 3

(a) Immunoreactive staining of Ki-67 and apoptotic cancer cells by Tunel in LNCaP tumors treated with finasteride. (b) The ratio of Ki-67-positive cancer cells in LNCaP tumors. Fibroblasts induced the expression of Ki-67 in cancer cells, and finasteride further promoted the expression of Ki-67 in the presence of fibroblasts. c-Jun is important in mediating the pro-proliferative effects of fibroblasts and finasteride. (c) The apoptotic index in LNCaP tumors. Fibroblasts induced the LNCaP cell apoptosis, and finasteride did not further promoted the LNCaP cell apoptosis in the presence of fibroblasts.

Figure 4

(a) Immunoreactive staining of Ki-67 and apoptotic cancer cells by Tunel in PC3 tumors (b) The ratio of Ki-67-positive cancer cells in PC3 tumors. Fibroblasts induced the expression of Ki-67; finasteride did not further promoted the expression of Ki-67 in the presence of wild fibroblasts. (c) The apoptotic index in PC3 tumors. Fibroblasts induced the PC3 cell apoptosis while finasteride repressed PC3 cell apoptosis in the presence of fibroblasts. c-Jun played a critical role in mediating the apoptosis-repressing effect of finasteride.

Figure 5

The expression of p-Akt and p-ERK1/2 in LNCaP (a) and PC3 (b) cells in mono-culture or in co-culture with fibroblasts or HPF in co-culture transwells. Finasteride repressed the expression of p-Akt and p-ERK1/2 in mono-culture of LNCaP (PC3) cells. However, when LNCaP (PC3) cells were grown with fibroblasts or HPF in co-culture transwell, Finasteride upregulated the expression of p-Akt and p-ERK1/2 in cancer cells. When c-Jun in fibroblasts was knocked out, the pro-proliferative effect of finasteride for LNCaP (PC3) cells was attenuated, especially for p-ERK1/2 in the same co-culture transwells.