Progesterone suppresses the progression of colonic carcinoma by increasing the activity of the GADD45α/JNK/c‑Jun signalling pathway

Abstract

Colorectal cancer (CRC) is the third most diagnosed cancer worldwide. Progesterone is associated with a decreased risk of CRC and leads to a favourable prognosis. However, the specific mechanism by which progesterone suppresses malignant progression remains to be elucidated. In the present study, the level of progesterone was first analysed in 77 patients with CRC, and immunohistochemistry was performed to detect the expression of progesterone receptor (PGR) in the paired specimens. The correlations between progesterone, PGR and CRC prognosis were assessed. A Cell Counting Kit-8 assay was then used to detect proliferation of the CRC cells. Flow cytometry was performed to estimate apoptosis and to evaluate the cycle of the CRC cells. A xenograft tumour model was established in nude mice to assess the role of progesterone in tumour growth. Finally, a PCR microarray was used to screen differentially expressed genes to further interpret the mechanism by which progesterone inhibits the malignant progression of CRC. It was found that low expression of progesterone and PGR were significantly associated with poor prognosis of CRC. In addition, progesterone suppressed CRC cell proliferation by arresting the cell cycle and inducing apoptosis in vitro . Moreover, the inhibitory role of progesterone in tumour growth was verified in vivo . Further investigation showed that the level of growth arrest and DNA damage-inducible protein α (GADD45α) was up-regulated by progesterone, and this was followed by the activation of the JNK pathway. Progesterone increased the activity of the JNK pathway via GADD45α to inhibit proliferation by arresting the cell cycle and inducing apoptosis, thereby suppressing the malignant progression of CRC. Therefore, it can be concluded that progesterone and PGR might act as inhibiting factors for poor prognosis of CRC.

Enhanced anti-cancer effects of oestrogen and progesterone co-therapy against colorectal cancer in males

“…The present data correlate with many earlier studies and emphasise the chemopreventive effects of E2 that could involve inhibition of CRC progression by ERβ-induced cell cycle arrest and apoptosis in malignant enterocytes ( 18 , 20 – 23 , 57 ). Our study also underscores the previously reported anti-cancer activities of P4 against CRC ( 19 , 24 , 25 , 56 ), which appear to be equal to those of E2 monotherapy, both in vivo and in vitro .…”

“…In contrast, elevated systemic testosterone levels and higher expression of ERα and AR proteins in CRC were associated with larger tumours, poor differentiation, advanced clinical stages, and worse outcomes in both genders ( 15 , 26 – 28 ). Hence, our data and results from prior reports ( 14 – 16 , 19 , 28 , 45 , 46 ) suggest that testosterone with AR and ERα could promote CRC development, while E2 and P4, alongside ERβ and PGR, may act as tumour suppressors.…”

“…Lower PGR expression in colonic neoplastic tissues was also associated with poor prognosis and significantly lower survival rates in both genders ( 55 ). Concurrently, P4 treatment inhibited growth in human LoVo, HT29, HCT116, SW480 and SW620, as well as, murine MC38 colon cancer cells by decreasing several cell cycle inducer proteins and cell survival markers, whilst simultaneously increasing cell cycle suppressors and pro-apoptotic molecules ( 19 , 24 , 25 ). Moreover, in vitro treatment with folic acid inhibited proliferation in COLO-205, HT29, and LoVo CRC cells by PGR-mediated pathways ( 56 ).…”

“…In agreement with our results, the risk of CRC increased by > 20% following oophorectomy and the odds augmented substantially with bilateral rather than unilateral ovariectomy ( 45 , 46 ). Moreover, higher serum levels of female reproductive steroid hormones alongside increased expression of ERβ and/or PGR in malignant tissues correlated with better prognosis in male and female CRC patients ( 14 , 16 – 19 ). In contrast, elevated systemic testosterone levels and higher expression of ERα and AR proteins in CRC were associated with larger tumours, poor differentiation, advanced clinical stages, and worse outcomes in both genders ( 15 , 26 – 28 ).…”

“…Additionally, normal colonic epithelium can generate and respond to sex steroid hormones, since enterocytes express the synthesising enzymes of 17β-oestradiol (E2), P4, and testosterone alongside their nuclear receptors (ERα, ERβ, PGR and AR) ( 12 – 15 ). Serum concentrations of E2 and/or P4 also correlated with significantly better prognosis in CRC patients, independent of their sex ( 14 , 16 – 19 ). In vitro and in vivo experimental studies have likewise demonstrated suppression of cell proliferation and survival following treatment with E2 and P4 by ERβ and/or PGR-mediated anti-cancer activities ( 18 – 25 ).…”