Taiwanin C selectively inhibits arecoline and 4‐NQO‐induced oral cancer cell proliferation via ERK1/2 inactivation

Abstract

Arecoline, the most abundant alkaloid in betel nut is known to promote abnormal proliferation of epithelial cells by enhancing epidermal growth factor receptor (EGFR) activation and cyclooxygenase-2 (COX2) expression. Taiwanin C, a naturally occurring lignan extracted from Taiwania cryptomerioides, has been found to be a potential inhibitor of COX2 expression. Based on the MTT assay results, taiwanin C was found to be effective in inhibiting the tumorous T28 cell than the non-tumorous N28 cells. The modulations in the expression of relevant proteins were determined to understand the mechanism induced by taiwanin C to inhibit T28 cell proliferation. The levels of activated EGFR and COX2 were found to be abnormally high in the T28 oral cancer cells. However, taiwanin C was found to inhibit the activation of EGFR and regulated other related downstream proteins and thereby inhibited the T28 cell proliferation. In conclusion the results indicate that taiwanin C suppresses COX2-EGFR and enhances P27 pathways to suppress arecoline induced oral cancer cell proliferation via ERK1/2 inactivation. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 62-69, 2017.

Down‐regulation of β‐catenin and the associated migration ability by Taiwanin C in arecoline and 4‐NQO‐induced oral cancer cells via GSK‐3β activation

“…In this study, we further demonstrate that treatment with Taiwanin C reduces nuclear accumulation of β‐catenin and thereby inhibits the transactivation of its target genes, including Cyclin D1, Tbx3, and c‐Myc (Figure ). Our previous in vitro studies on T28 cells showed that Taiwanin C treatment causes G1 phase arrest and inhibits the proliferation of T28 cells by suitably regulating p27 and cyclin D1 . Similarly, the present results on the in vivo study show that Taiwanin C enhances the expression of p27 and suppresses the cyclin D1 levels.…”

Taiwanin C elicits apoptosis in arecoline and 4‐nitroquinoline‐1‐oxide‐induced oral squamous cell carcinoma cells and hinders proliferation via epidermal growth factor receptor/PI3K suppression

“…These finding suggest that the mechanism of action of Taiwanin C in the inhibition of PGE 2 production is mediated through the inhibition of COX‐2 enzymatic activity . Taiwanin C is known to stimulate an ERK1/2 dependent elevation of p27 levels and thereby hinders the G1‐S phase transition in T28 cells cell . In this study, we also found that Taiwanin C also suppresses the level of p21‐a cyclin dependent kinase inhibitor that potentially inhibits all cyclin/CDK complexes (Figure ).…”

“…In our experiments, OSCC model generated C57BL/6JNarl male mice by treating with 0.5 mg/mL arecoline, as well as in combination with 0.2 mg/mL 4‐NQO. In this OSCC model in C57BL/6JNarl male mice primary cells, our previous study observed that EGFR over expressiont maybe the major leading cause of abnormal proliferation in T28 primary oral cancer cell . Moreover, it has been reported that the activity of COX‐2 was inhibited by Taiwanin C, reflecting the inhibition of COX‐2 dependent PGE 2 production.…”

“…15 Our previous findings show that Taiwanin C selectively targets tumorous oral squamous cell carcinoma (OSSC) and not non-tumor cells and have also shown that Taiwanin C inhibits migratory properties of tumorous OSSCs. 16,17 Previous findings also indicated that COX-2 is upregulated during malignant transition of the oral mucosa and that it is some manner related to the development of genomic instability, and is one of the important cellular factors in promoting cancer development and progression. 18 Epidermal growth factor receptor is upregulated in many types of human tumors, particularly head and neck squamous cell carcinoma.…”

Taiwanin E inhibits cell migration in human LoVo colon cancer cells by suppressing MMP-2/9 expression via p38 MAPK pathway

“…Taiwanin E, is a phenolic lignan lactone isolated from T. cryptomerioides with proven anti‐proliferative potential and capacity to induce cell cycle arrest in cancer cells (Wang et al, ). Previous studies on oral squamous cells showed that another related lignan Taiwanin C selectively inhibit cell proliferation in tumor cells with relatively no effect on the non‐tumor cells (Lin et al, ; Hsieh et al, ). Taiwanin C has also been proven to inhibit squamous cell metastasis by modulating wnt/β‐catenin signal transduction (Hsieh et al, ).…”