RESUMEN
Colorectal cancer is a global malignancy with a high incidence and mortality rate. THZ2, a small inhibitor targeted CDK7, could inhibit multiple human tumor growths including small cell lung cancer, triple-negative breast cancer, ovarian cancer. However, the effect of THZ2 on inflammation, especially on colitis-associated colorectal cancer, is still unknown. In this study, we assessed the anti-inflammatory and anti-tumor effect of THZ2 in the mouse models of dextran sulfate sodium (DSS)-induced acute colitis and azoxymethane (AOM)/DSS-induced colitis-associated colorectal cancer. We found that THZ2 ameliorated inflammatory symptoms, including bleeding and diarrhea, in mouse models of DSS-induced acute colitis and AOM/DSS-induced colorectal cancer. The results of Western blot and immunohistochemistry showed that THZ2 rescued the up-regulated expression of COX2, IL-6, ß-catenin, and snail in the mouse models. Moreover, THZ2 inhibits the development of colorectal cancer in the mouse model of AOM/DSS-induced colitis-associated colorectal cancer. Generally, THZ2 not only can inhibit DSS-induced colitis, but also can hinder AOM/DSS-induced colorectal cancer.
RESUMEN
Colorectal cancer is a common malignant tumor. A major factor in the high mortality rate of colorectal cancer is the emergence of multidrug resistance (MDR). Overexpression of the ABCG2 gene in cancer cells directly leads to MDR. Finding new inhibitors of ABCG2 may be an effective way to overcome drug resistance. We found that the compound GSK2606414 enhanced the sensitivity of the ABCG2 substrate to the chemotherapeutic drugs mitoxantrone and doxorubicin in ABCG2-overexpressing multidrug-resistant colorectal cancer cells by increasing their intracellular accumulation without affecting the protein expression of ABCG2. Molecular docking experiments predicted that GSK2606414 could stably bind in the drug-binding pocket of ABCG2. In conclusion, GSK2606414 can sensitize ABCG2-overexpressed multidrug-resistant colorectal cancer cells to chemotherapy drugs and can be used as a potential inhibitor of ABCG2.
RESUMEN
The process of protein ubiquitination and deubiquitination plays an important role in maintaining protein stability and regulating signal pathways, and protein homeostasis perturbations may induce a variety of diseases. The deubiquitination process removes ubiquitin molecules from the protein, which requires the participation of deubiquitinating enzymes (DUBs). Ubiquitin-specific protease 15 (USP15) is a DUB that participates in many biological cell processes and regulates tumorigenesis. A dislocation catalytic triplet was observed in the USP15 structure, a conformation not observed in other USPs, except USP7, which makes USP15 appear to be unique. USP15 has been reported to be involved in the regulation of various cancers and diseases, and the reported substrate functions of USP15 are conflicting, suggesting that USP15 may act as both an oncogene and a tumor suppressor in different contexts. The importance and complexity of USP15 in the pathological processes remains unclear. Therefore, we reviewed the diverse biological functions of USP15 in cancers and other diseases, suggesting the potential of USP15 as an attractive therapeutic target.
