POLYPHENOLS AND THE HH/GLI SIGNALING PATHWAY IN CANCER CELLS − Rakyat Biologi

HH signaling pathway plays an important role in the carcinogenesis of medulloblastoma, an aggressive tumor of the cerebellum (131). A study by Elamin and co-workers investigated the effects of curcumin on medulloblastoma cells, and in particular its effects on the HH pathway. The authors demonstrated that curcumin had dose-dependent anti-proliferative and cytotoxic effects on four different medulloblastoma cell lines (MED-1, MED-4, MED-5 and DAOY). In addition, curcumin was able to increase the percentage of cells at the G2/M phase of the cell cycle. They also reported that curcumin (40 µM) was able to down-regulate the expression level of SHH protein (down-regulation of 12.5-fold after 8h of treatment) and its direct downstream targets GLI1 and PTCH1. The level of GLI1 and PTCH1 decreased more than 5 and 2-fold respectively, as compared to the control untreated cells. Moreover, it was shown that curcumin inhibited Akt/NF-κB and β-catenin pathways and triggered apoptosis through the down-regulation of Bcl-2, a downstream effector of HH pathway (132).

Chondrosarcoma, which shows abnormal activity of the human Indian Hedgehog (hIHH) signaling pathway, is a primary bone tumor with a poor prognosis (133). A recent study by Tang et al. investigated the effects of EGCG on growth and apoptosis of chondrosarcoma cells. They assessed that EGCG was able to affect proliferation and to induce apoptosis of SW1353 and CRL-7891 human chondrosarcoma cells in a dose-dependent manner. Moreover, they demonstrated that EGCG inhibited the hIHH pathway in these cell lines, through the down-regulation of PTCH1 and GLI1 mRNA and protein levels in a dose-dependent manner. These results suggest that EGCG could be a promising therapeutic agent for chondrosarcomas (134).

Another report by Slusarz et al. investigated the effect of seven polyphenols on prostate cancer: apigenin, baicalein, curcumin, EGCG, genistein, quercetin, and resveratrol. These compounds were individually able to inhibit the in vitro growth of PC3 and LNCaP human prostate cancer cell lines (135). In addition they were individually able to inhibit the growth of the mouse prostate cancer cell line TRAMP-C2 and to reduce or delay prostate cancer growth in vivo in TRAMP mice, when fed in combination. Moreover, the authors investigated the in vitro effects of these seven compounds on the HH pathway in two different cell assays, employing TRAMP-C2 and SHH Light II cells. Curcumin, genistein, EGCG and resveratrol were able to inhibit the HH signaling pathway in both cell assays, through the down-regulation of basal GLI1 mRNA expression in TRAMP-C2 cells and through the down-regulation of GLI reporter activity in the SHH Light II cell line. Conversely, apigenin, baicalein and quercetin, were able to decrease GLI1 mRNA expression in TRAMP-C2 cells, but not the GLI reporter activity in the SHH Light II cell line. Thus, the authors proposed that the effects of these polyphenols on prostate cancer cells might result from inhibition of the HH pathway (136).

Cancer stem cells (CSCs) play a key role in the carcinogenesis and progression of prostate cancer (137). Recent studies have shown that the activation of the HH pathway is involved in the regulation of pancreatic CSCs (138,139) and that polyphenols have anti-cancer stem cells (CSC) effects (140,141). A study by Tang et al. investigated the effects of the treatment with EGCG in pancreatic CSCs. Their results showed that EGCG was able to inhibit the growth and invasion of pancreatic CSCs and to induce apoptosis in these cells. Moreover, EGCG inhibited the HH pathway through the suppression of SMO, PTCH1, PTCH2, GLI-1 and GLI-2 expression and through the inhibition of GLI transcriptional activity. In addition, EGCG inhibited the nuclear expression of GLI1 and GLI2 proteins and quercetin synergized with EGCG in inhibiting GLI transcriptional and TCF/LEF activities, leading to the inhibition of self-renewal capacity of pancreatic CSCs (142). Similarly, Zhang et al. investigated the effects of genistein on the stemness properties of pancreatic CSCs. Genistein was able to inhibit tumorsphere formation and colony formation of prostate cancer cells and to suppress tumorigenicity in vivo. Moreover, the authors demonstrated that these effects of genistein were due to the down-regulation of the HH pathway. In fact, they found that the HH pathway plays an important role in the maintenance of pancreatic CSCs and that genistein was able to affect this pathway by down-regulating GLI1 mRNA and protein levels in a dose-dependent manner. They also demonstrated by immunohistochemistry that the treatment with genistein decreased the GLI1 protein expression level in pancreatic cancer tissue. Thus, they concluded that genistein could be a therapeutic agent for its capacity to affect the HH pathway, leading to the loss of stemness properties of pancreatic CSCs (143).