Though Farnesiferol C (FC) derived from Ferula asafoetida is known to have antiangiogenic and apoptotic effect in gastric, breast, nonsmall lung cancers, the underlying antitumor mechanism of FC is not fully understood so far. Hence, in the current study, apoptotic mechanism of FC was explored in colon cancers in association with carbon catabolite repression 4-negative on TATA-less 2 (CNOT2)/c-Myc signaling. Herein FC significantly increased cytotoxicity and reduced the number of colonies in HCT116 cells more effectively than in SW480 cells, though FC enhanced sub-G1 cell population in HCT116 and SW480 cells compared to untreated control. Consistently, FC activated the cleavages of Poly ADP-ribose polymerase (PARP) and Bax and attenuated the expression of pro-PARP and Cyclin D1 in HCT116 cells better than SW480 cells. Also, FC significantly reduced the expression of CNOT2 and c-Myc. Also, FC reduced of c-Myc stability in HCT116 cells by cycloheximide assay. Notably, CNOT2 depletion reduced the expression of c-Myc, while c-Myc depletion also attenuated the expression of CNOT2 in HCT116 cells, implying the crosstalk between CNOT2 and c-Myc. Furthermore, overexpression of c-Myc or CNOT2 promoted the expression of pro-PARP in HCT116 cells. Overall, these findings suggest that FC induces apoptosis via inhibition of CNOT2 and c-Myc in colon cancers for a potent anticancer candidate for further agriculture cultivation in Korea.

In this study, we elucidated the molecular mechanism of silymarin by which silymarin may inhibits cell proliferation in human colorectal cancer cells in order to search the new potential anti-cancer target associated with the cell growth arrest. Silymarin reduced the level of c-Myc protein but not mRNA level indicating that silymarin-mediated downregulation of c-Myc may result from the proteasomal degradation. In the confirmation of silymarin-mediated c-Myc degradation, MG132 as a proteasome inhibitor attenuated c-Myc degradation by silymarin. In addition, silymarin phosphorylated the threonine-58 (Thr58) of c-Myc and the point mutation of Thr58 to alanine blocked its degradation by silymarin, which indicates that Thr58 phosphorylation may be an important modification for silymarin-mediated c-Myc degradation. We observed that the inhibition of ERK1/2, p38 and GSK3β blocked the Thr58 phosphorylation and subsequent c-Myc degradation by silymarin. Finally, the point mutation of Thr58 to alanine attenuated silymarin-mediated inhibition of the cell growth. The results suggest that silymarin induces the cell growth arrest through c-Myc proteasomal degradation via ERK1/2, p38 and GSK3β-dependent Thr58 phosphorylation.

The flower buds of Sophora japonica L (SF), as a well-known traditional Chinese medicinal herb, have been used to treat bleeding-related disorders such as hematochezia, hemorrhoidal bleeding, dysfunctional uterine bleeding, and diarrhea. However, no specific anti-cancer effect and its molecular mechanism of SF have been described. Thus, we performed in vitro study to investigate if treatment of SF affects activating transcription factor 3 (ATF3) expression and ATF3-mediated apoptosis in human colorectal cancer cells. The effects of SF on cell viability and apoptosis were measured by MTT assay and Western blot analysis against cleaved poly (ADP-ribose) polymerase (PARP). ATF3 activation induced by SF was evaluated using Western blot analysis, RT-PCR and ATF3 promoter assay. SF treatment caused decrease of cell viability and increase of apoptosis in a dose-dependent manner in HCT116 and SW480 cells. Exposure of SF activated the levels of ATF3 protein and mRNA via transcriptional regulation in HCT116 and SW480 cells. Inhibition of extracellular signal-regulated kinases (ERK) 1/2 by PD98059 and p38 by SB203580 attenuated SF-induced ATF3 expression and transcriptional activation. Ectopic ATF3 overexpression accelerated SF-induced cleavage of PARP. These findings suggest that SF-mediated apoptosis may be the result of ATF3 expression through ERK1/2 and p38-mediated transcriptional activation.