Abstract
ObjectiveSuppression of bromodomain and extra terminal (BET) proteins has a bright prospect to treat MYC-driven tumors. Bromodomain containing 4 (BRD4) is one of the BET proteins. ARV-825, consisting of a BRD4 inhibitor conjugated with a cereblon ligand using proteolysis-targeting chimera (PROTAC) technology, was proven to decrease the tumor growth effectively and continuously. Nevertheless, the efficacy and mechanisms of ARV-825 in gastric cancer are still poorly understood.MethodsCell counting kit 8 assay, lentivirus infection, Western blotting analysis, Annexin V/propidium iodide (PI) staining, RNA sequencing, a xenograft model, and immunohistochemistry were used to assess the efficacy of ARV-825 in cell level and animal model.ResultsThe messenger RNA (mRNA) expression of BRD4 in gastric cancer raised significantly than those in normal tissues, which suggested poor outcome of patients with gastric cancer. ARV-825 displayed higher anticancer efficiency in gastric cancer cells than OTX015 and JQ1. ARV-825 could inhibit cell growth, inducing cell cycle block and apoptosis in vitro. ARV-825 induced degradation of BRD4, BRD2, BRD3, c-MYC, and polo-like kinase 1 (PLK1) proteins in four gastric cancer cell lines. In addition, cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP) was elevated. Knockdown or overexpression CRBN could increase or decrease, respectively, the ARV-825 IC50 of gastric cancer cells. ARV-825 reduced MYC and PLK1 expression in gastric cancer cells. ARV-825 treatment significantly reduced tumor growth without toxic side effects and downregulated the expression of BRD4 in vivo.ConclusionsHigh mRNA expression of BRD4 in gastric cancer indicated poor prognosis. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells via transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.
Highlights
According to the latest World Cancer Report released by the World Health Organization Research Agency for 2020, gastric cancer ranked fifth in the incidence of most common cancers worldwide [1]
Expression of BRD4 was measured in different kinds of tumors, which was displayed using gene expression profiling interactive analysis (GEPIA, http://gepia.cancer-pku.cn/ index.html), which illustrated that mRNA expression of BRD4 in tumor tissue was raised remarkably than that in normal tissue only in stomach adenocarcinoma (STAD) and esophageal adenocarcinoma (ESCA, Figure 1A)
BRD4, BRD2, and BRD3 were abundantly expressed in MGC803, HGC27, AGS, SGC7901, BGC823, and SNU-216 cells (Figure 2A), implying that the BET proteins were diffusely expressed in gastric cancer cells
Summary
According to the latest World Cancer Report released by the World Health Organization Research Agency for 2020, gastric cancer ranked fifth in the incidence of most common cancers worldwide [1]. In 2015, the crude incidence of gastric cancer in China ranked second among common malignant tumors. The mortality rate of gastric cancer was 21.16 per 100,000, in China in 2015, ranking third among malignant tumors [2]. In order to solve various problems in cancer treatment, many studies provided direction for our treatment of gastric cancer, such as polarized macrophages, for enhancing tumor targeting and drug sensitivity [5, 6], induced pluripotent stem cells (iPS) enhancing immunotherapy against cancer [7], and review in tumor microenvironment [8]
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
