Abstract
Baicalin is a natural flavonoid glycoside which has potent anti-tumor and antioxidant activity in cancer cells. In the present study, we found that baicalin treatment significantly induced senescence in colon cancer cells. Furthermore, baicalin upregulated the expression of decidual protein induced by progesterone (DEPP) in HCT116 colon cancer cells, which accompanied with the activation of Ras/Raf/MEK/ERK and p16INK4A/Rb signaling pathways. Meanwhile, these phenomena also appeared under the anti-oxidation effect exerted by baicalin. In addition, ectopic expression of DEPP in HCT116 cells significantly induced the activity of senescence-associated β-galactosidase (SA-β-Gal) in tumor cells regulated by Ras/Raf/MEK/ERK signaling pathway. Knockdown of DEPP by RNA interference efficiently counteracted the baicalin-mediated growth inhibition, senescence and cell cycle arrest in cancer cells. Importantly, in a xenograft mouse model of human colon cancer, we further confirmed that baicalin treatment dramatically inhibited tumor growth, which was due to the induction of tumor cellular senescence via the upregulation of DEPP and the activation of Ras/Raf/MEK/ERK signaling in vivo. In addition to baicalin treatment, we found that the hypoxia-response protein DEPP functions as a positive regulator involving the regulations of Ras/Raf/MEK/ERK signaling pathway and inhibition of human colon cancer by other anti-oxidative drugs, such as curcumin and sulforaphane, resulting in tumor cellular senescence. These results collectively suggest that baicalin upregulates the expression of DEPP and activates its downstream Ras/Raf/MEK/ERK and p16INK4A/Rb pathways by acting as an antioxidant, leading to senescence in colon cancer cells.
Highlights
A growing amount of evidence has demonstrated that senescence is a crucial tumor-suppressive approach in Recently, evidence suggests that oncogene Ras, an upstream adaptor of the Ras/Raf/MEK/ERK pathway, is relevant for the accumulation of p16INK4A and Official journal of the Cell Death Differentiation AssociationWang et al Cell Death and Disease (2018)9:217 dephosphorylation of pRb, thereby promoting cellular senescence[13]
To further validate whether the inhibition of cancer cells mediated by baicalin is due to its induced senescence in human colon cancer cells, HCT116 and SW480 treated with baicalin at different concentrations for 48 h and the acidic βgalactosidase activity was analyzed by senescenceassociated β-galactosidase (SA-β-gal) staining
Our current study demonstrated that baicalin intensively induced hypoxia-like phenomenon of low reactive oxidative species (ROS) level in colon cancer cells, due to the enhanced superoxide dismutase (SOD) activity
Summary
A growing amount of evidence has demonstrated that senescence is a crucial tumor-suppressive approach in Recently, evidence suggests that oncogene Ras, an upstream adaptor of the Ras/Raf/MEK/ERK pathway, is relevant for the accumulation of p16INK4A and Official journal of the Cell Death Differentiation AssociationWang et al Cell Death and Disease (2018)9:217 dephosphorylation of pRb, thereby promoting cellular senescence[13]. Only concepts related to oncogene, such as Ras, indirectly support that high degree of hypoxia may induce senescence in cancer cells, without clear experimental validation[19]. Several hypoxia-response genes involved in cell cycle control, stress response and angiogenesis have been identified in the malignant glioma cell line U-251, such as Cyclin G2, v-Fos, DNA damage-inducible transcript 3, Glutathione S-transferase and DEPP20. None of these genes have been reported to be relevant for cellular senescence. The functional role of DEPP in senescence induction in cancer cells mediated by baicalin is unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
