Abstract
BackgroundBecause twigs of Cinnamomum cassia (TC) have been reported to exert anti-cancer activity, the mechanistic study for TC’s anti-cancer activity is required. Thus, we elucidated the potential molecular mechanism of TC’s anti-proliferative effect and the induction of apoptosis in human colorectal cancer cells.MethodsHow water extracts form TC (TC-HW) was used in this study. Anti-cell proliferative effect of TC-HW was evaluated by MTT assay. The change of protein or mRNA level by TC-HW was evaluated by Western blot and RT-RCR, respectively. The promoter construct for ATF3, NF-κB, TOP-FLASH or FOP-FLASH was used for the investigation of the transcriptional activity for ATF3, NF-κB or Wnt. siRNA for ATF3 or p65 was used for the knockdown of ATF3 and p65.ResultsTC-HW reduced the cell viability in human colorectal cancer cells. TC-HW decreased cyclin D1 protein level through cyclin D1 degradation via GSK3β-dependent threonine-286 (T286) phosphorylation of cyclin D1, indicating that cyclin D1 degradation may contribute to TC-HW-mediated decrease of cyclin D1 protein level. TC-HW downregulated the expression of cyclin D1 mRNA level and inhibited Wnt activation through the downregulation of β-catenin and TCF4 expression, indicating that inhibition of cyclin D1 transcription may also result in TC-HW-mediated decrease of cyclin D1 protein level. In addition, TC-HW was observed to induce apoptosis through ROS-dependent DNA damage. TC-HW-induced ROS increased NF-κB and ATF3 activation, and inhibition of NF-κB and ATF3 activation attenuated TC-HW-mediated apoptosis.ConclusionsOur results suggest that TC-HW may suppress cell proliferation through the downregulation of cyclin D1 via proteasomal degradation and transcriptional inhibition, and may induce apoptosis through ROS-dependent NF-κB and ATF3 activation. These effects of TC-HW may contribute to the reduction of cell viability in human colorectal cancer cells. From these findings, TC-HW has potential to be a candidate for the development of chemoprevention or therapeutic agents for human colorectal cancer.
Highlights
Because twigs of Cinnamomum cassia (TC) have been reported to exert anti-cancer activity, the mechanistic study for TC’s anti-cancer activity is required
Effect of TC-HW on the cell viability and cyclin D1 protein level in HCT116 and SW480 cells To evaluate whether TC-HW reduces cell viability in human colorectal cancer cell lines, HCT116, SW480, LoVo and HT-29 cells, MTT assay was performed
Because cell growth arrest contributes to the decrease of the cell viability, we investigated whether TC-HW modulates cyclin D1 protein level in HCT116 and SW480 cells because cyclin D1 has been regarded as one of the proteins regulating the cell proliferation
Summary
Because twigs of Cinnamomum cassia (TC) have been reported to exert anti-cancer activity, the mechanistic study for TC’s anti-cancer activity is required. We elucidated the potential molecular mechanism of TC’s anti-proliferative effect and the induction of apoptosis in human colorectal cancer cells. According to the many literatures, twigs of C. cassia (TC) exert the pharmacological activities such as anti-allergy, insecticidal, antimicrobial, antiulcer, anti-inflammatory, vasodilatory, immune-suppressive, and neuronal death prevention, tyrosinase inhibition and anticancer, antioxidant and free radical scavenging, as well as antidiabetic and aldose reductase inhibition activities [15]. Additional molecular mechanism for the anticancer activity of TC still remains to be elucidated. We elucidated anti-cancer activity and potential molecular mechanism of TC against human colorectal cancer cells. We here reported the additional mechanism of hot-water extracts from the twigs of Cinnamomum cassia (TC-HW) for anti-cancer activity. TC-HW suppressed the proliferation of human colorectal cancer cells through GSK3βdependent cyclin D1 degradation and induced ROSdependent apoptosis in human colorectal cancer cells
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