Andrographolide inhibits Burkitt's lymphoma by binding JUN and CASP3 proteins.

BACKGROUND: Burkitt's lymphoma, one of the most common subtypes of pediatric malignant lymphoma, is notorious for its swift onset, aggressive proliferation, pronounced invasiveness, and marked malignancy. The therapeutic landscape for Burkitt's lymphoma currently falls short of providing universally effective and tolerable solutions. Andrographolide, a primary active component of Andrographis paniculata, is renowned for its properties of heat-clearing, detoxification, inflammation reduction, and pain relief. It is predominantly used in treating bacterial and viral infections of the upper respiratory tract, as well as dysentery. Various reports highlight the antitumor effects of andrographolide. Yet, its specific impact and the underlying mechanism of action on Burkitt's lymphoma remain an uncharted area of research. METHOD: We employed network pharmacology to pinpoint the targets of andrographolide's action on Burkitt's lymphoma and the associated pathways. We then evaluated the impact of andrographolide on Burkitt's lymphoma using both in vitro and in vivo patient-derived xenograft (PDX) models. Concurrently, we confirmed the molecular targets of andrographolide in Burkitt's lymphoma through immunofluorescence assays. RESULT: Utilizing network pharmacology, we identified 15 relevant targets, 60 interrelationships between these targets, and numerous associated signaling pathways for andrographolide's action on Burkitt's lymphoma. In vitro efficacy tests using High-throughput Drug Sensitivity Testing and in vivo PDX model evaluations revealed that andrographolide effectively curtailed the growth of Burkitt's lymphoma. Moreover, we observed a increased in the expression of JUN (c-Jun) and CASP3 (Caspase 3) proteins in Burkitt's lymphoma cells treated with andrographolide. CONCLUSION: Andrographolide inhibits the growth of Burkitt's lymphoma by inhibiting JUN and CASP3 proteins.

Circ_0046599 Promotes the Development of Hepatocellular Carcinoma by Regulating the miR-1258/RPN2 Network.

BACKGROUND: Many studies have confirmed that circular RNAs (circRNAs) play a key role in the biological progression of cancers. However, the function of a novel circRNA, circ_0046599, in hepatocellular carcinoma (HCC) progression has not been explored. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure the expression of circ_0046599, microRNA (miR)-1258 and Ribophorin II (RPN2). Subcellular fractionation location assay was used to localize circ_0046599 in HCC cells. The circular characteristic of circ_0046599 was verified using Ribonuclease R (RNase R) digestion assay. Besides, cell counting kit 8 (CCK8) assay, colony formation assay, wound healing assay and transwell assay were used to detect cell proliferation, migration and invasion, respectively. The lactate production and glucose level were determined by Lactate and Glucose Assay Kits. Furthermore, the protein levels of glycolysis, metastasis and proliferation-related marker proteins, as well as RPN2 were tested by Western blot (WB) analysis. Moreover, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were employed to confirm the interactions among circ_0046599, miR-1258 and RPN2. In addition, mice xenograft models were applied to observe the effect of circ_0046599 silencing on HCC tumor growth in vivo. RESULTS: Circ_0046599 was highly expressed in HCC tissues and cells, and its knockdown could suppress HCC cell proliferation, migration, invasion and glycolysis process. MiR-1258 could be targeted by circ_0046599, and its inhibitor could invert the suppressing effect of circ_0046599 knockdown on HCC progression. Further, RPN2 was a target of miR-1258. Overexpressed RPN2 could reverse the inhibiting effect of miR-1258 overexpression on HCC progression. Also, knockdown of circ_0046599 could restrain HCC tumor growth in vivo. CONCLUSION: Our results provided new evidence that circ_0046599 could promote the progression of HCC by increasing RPN2 expression via sponging miR-1258.

CHSY1 promoted proliferation and suppressed apoptosis in colorectal cancer through regulation of the NFκB and/or caspase-3/7 signaling pathway.

Colorectal cancer is a commonly observed malignant cancer. However, the limited therapies for colorectal cancer do not bring much benefit for patients. Chondroitin synthase-1 (CHSY1) is an enzyme responsible for the biosynthesis of chondroitin sulfate and has been implicated in the tumorigenesis of several cancer types; however, there is limited information regarding the role of CHSY1 in colorectal cancer. In the present study, CHSY1 was demonstrated to be highly expressed in colorectal cancer tissues and in cell lines, and the CHSY1 expression level was associated with the 5-year survival rate of patients with colorectal cancer. Following CHSY1 knockdown, the proliferation of colorectal cancer cells was significantly decreased. The number of RKO cells decreased by 50% following CHSY1 knockdown compared with that in the control after culture for 5 days. However, the apoptosis rate of RKO cells increased to 14.15% after CHSY1 knockdown. In addition, the activity of caspase-3/7 was also enhanced. Furthermore, the expression of B-cell lymphoma 2 (Bcl-2) was reduced, whereas the levels of Bcl-2-associated X protein (Bax) and truncated caspase-3/7 were increased following CHSY1 knockdown. Additionally, the phosphorylation level of IκB and the expression of nuclear factor (NF)κB also decreased. In contrast, forced expression of CHSY1 increased the level of Bcl-2, NFκB, and phosphorylated IκB, whereas the level of bax and truncated caspase-3/7 decreased. Therefore, the data of the present study suggest that CHSY1 promoted cell proliferation by regulating NFκB signaling and suppressed cell apoptosis by regulating/caspase-3/7 signaling in colorectal cancer. The present study also suggests that CHSY1 may be a potential target for colorectal cancer therapy.