| Colon cancer is a common malignant tumor in the human digestive system.The incidence of colon cancer is closely related to the economic development of the region and the people’s eating habits.When cancer is diagnosed,distant metastases are often found.Therefore,in addition to surgical treatment,finding more effective chemotherapy drugs to prevent recurrence and metastasis is the primary task in colon cancer chemotherapy.In modern scientific research,many natural Chinese herbal medicines have become supplements and replacements for clinical drugs,or as health products and nutritional products,used to reduce the toxic and side effects of chemotherapy drugs on patients in cancer treatment.Moreover,many natural Chinese herbs and their extracts can cause cell senescence,apoptosis or activate complement-mediated apoptosis pathways,and then exert anti-tumor effects.Curcumin is a fat-soluble polyphenolic compound obtained from the roots and stems of the genus Curcuma longa L.Curcumin has anti-inflammatory,anti-oxidation,anti-cancer and other biological activities,and showed good safety,causing widespread concern.Among them,curcumin is particularly useful for anti-tumor treatment.Shikonin,another natural Chinese herbal extract,is the main active ingredient isolated from the traditional Chinese herbal medicine comfrey,which belongs to naphthoquinone compounds.It also has a variety of biological activities and also has anti-inflammatory and anti-tumor properties.Studies have found that these two common Chinese herbal extracts can induce apoptosis in colon cancer cells,but the mechanisms that induce apoptosis and exert anti-tumor effects need to be further studied and explored.Autophagy is a way of self-degradation of cells,which is the process of transporting damaged organelles and macromolecules to lysosome digestion and degradation.Autophagy can break down macromolecules in cells,producing intermediates necessary for decomposition and anabolic processes;and recombining new cells by degrading normal proteins.Moreover,autophagy can prevent intracellular chromosomal abnormalities and maintain genomic stability.Autophagy is a "double-edged sword" in tumors,which plays a dual role.The role of autophagy depends on the biological factors such as tumor type,oncogene and tumor suppressor gene and the technical factors such as model system.In recent years,some studies have shown that the regulation of Hippo signaling pathways on organ development and other processes is achieved by regulating cell proliferation and apoptosis.Recent studies have shown that the Hippo signaling pathway also plays an important role in tumorigenesis,progression and metastasis.The YAP(Yes-associated protein)is a transcriptional coactivator in the Hippo signaling pathway.The Hippo signaling pathway leads to the degradation of YAP in the cytoplasm by participating in a series of kinase activation processes;non-phosphorylated YAP enters the nucleus involved in transcription factor activation.YAP is also involved in tumor biological behaviors such as epithelial-mesenchymal transition,migration,invasion and chemoresistance of tumor cells.Studies have shown that YAP is involved in inducing cell autophagy and tumor development,but the mechanism by which it induces cell autophagy is unclear.Therefore,an in-depth study of YAP’s involvement in the regulation of autophagy and related molecular mechanisms in colon cancer cells will help us find new targets related to colon cancer treatment.This topic is divided into two parts.The first part is to study the action mechanism of curcumin on colon cancer cells,and we found that curcumin from traditional Chinese herbal medicine can induce autophagy in human colon cancer cells HCT116 and SW620.At the same time,curcumin can also significantly reduce the expression of YAP protein in colon cancer cells.When we overexpressed the YAP in colon cancer cells in experiments,we found that overexpression of YAP reversed the curcumin’s inhibition of colon cancer cell proliferation and the induction of autophagy.Even so,compared with the blank control group,the addition of curcumin to colon cancer cells overexpressing YAP still significantly inhibited cell proliferation and induced autophagy.At the same time,we found that curcumin down-regulates the expression of YAP in cells by activating the Hippo signaling pathway.When we knocked down the YAP in colon cancer cells in the experiments,curcumin significantly increased the inhibition of cell proliferation and the promotion of cell autophagy.Therefore,we speculated that curcumin may act on YAP and regulate the corresponding cell signaling pathways to activate death autophagy of colon cancer cells.Through subsequent experiments,we found that curcumin induces death autophagy of colon cancer cells by inhibiting IGF1/PI3K/Ak/mTOR signaling pathway activity after down-regulating YAP.This study also conducted a nude mice tumor formation experiment.The result shows that knocking down the YAP can inhibit the colon cancer cell proliferation in vivo,and the combined effect of curcumin treatment and low expression of YAP makes the colon cancer cell proliferation inhibition in vivo more obvious.In the second part,we studied the effect of shikonin,another natural Chinese herbal medicine extract,on colon cancer cell autophagy in vitro and the regulation of YAP.We also found that shikonin induced autophagy in human colon cancer cells HCT116 and SW620 and inhibited colon cancer cell proliferation.At the same time,shikonin also reduced YAP protein expression in colon cancer cells.In subsequent molecular mechanism studies,we know from experimental results that shikonin down-regulates YAP expression by activating the Hippo signaling pathway;and induces autophagy in colon cancer cells by inhibiting PI3K/Akt/mTOR signaling pathway activity.In summary,YAP may play an important role in curcumin and shikonin’s anti-colon cancer,and we believe that YAP may be a potential diagnostic marker for colon cancer. |
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