Previously, we demonstrated that
folic acid (FA) could inhibit proliferation of
colorectal cancer cell lines through activating the
folate receptor (FR)α/cSrc/ERK1/2/NFκB/p53 pathway and anti-COLO-205
tumor growth in vivo. Since we recently also demonstrated that female
sex hormones could affect the FA's action in regulating endothelial cell proliferation and migration, the aim of this study was to investigate the effect of
progesterone (P4) on the FA-induced anti-proliferation in
colorectal cancer cells. Treatment with FA significantly reduced the proliferation of the P4 receptor (PR)-positive
colon cancer cell lines, COLO-205, HT-29 and LoVo, but did not significantly affect the proliferation of the PR-negative
colon cancer cell lines, HCT116 and DLD-1. Pre-treatment with
Org 31710, a PR specific antagonist, abolished the FA-induced proliferation inhibition and activation in the signaling pathway involved in regulating proliferation inhibition in these PR positive
colorectal cancer cell lines. The involvement of PR in the FA-induced activation of cSrc and up-regulations in cell cycle inhibitory
proteins (p21, p27 and p53) was confirmed by knock-down of PR expression using the
siRNA technique. Importantly, we show direct
protein interaction between FR and PR in COLO-205. Moreover, treatment with FA induced PR activation in COLO-205. Taken together, these data suggest that FA induced proliferation inhibition in
colon cancer cells through activation of PR. This finding might explain some of the controversies of FA's effects on
cancer growth and provide valuable reference for clinical applications of FA in treating
colorectal cancer.