Ribavirin inhibits the growth and ascites formation of hepatocellular carcinoma through downregulation of type I CARM1 and type II PRMT5.

Type I co-activator-associated arginine methyltransferase 1 (CARM1) and type II protein arginine methyltransferase 5 (PRMT5) are highly expressed in multiple cancers including liver cancer and their overexpression contributes to poor prognosis, thus making them promising therapeutic targets. Here, we evaluated anti-tumor activity of ribavirin in hepatocellular carcinoma (HCC). We found that ribavirin significantly inhibited the proliferation of HCC cells in a time- and dose-dependent manner. Furthermore, ribavirin suppressed the growth of subcutaneous and orthotopic xenograft of HCC in mice, decreased vascular endothelial growth factor (VEGF) and peritoneal permeability to reduce ascites production, and prolonged the survival of mice in HCC ascites tumor models. Mechanistically, ribavirin potently down-regulated global protein expression of CARM1 and PRMT5, and concurrently decreased accumulation of H3R17me2a and H3R8me2s/H4R3me2s. However, ribavirin did not affect the activity and mRNA levels of both CARM1 and PRMT5 in vivo and in vitro HCC cells. In addition, our ChIP results shown that ribavirin inhibited CARM1 which in turn decreased the H3R17me2a, binds to the eukaryotic translation initiation factor 4E (eIF4E) and VEGF promoter region, and reduced the relative mRNA expression level of eIF4E and VEGF in HCC cells. Our findings suggested a potential therapeutic strategy for patients with HCC through inhibition of the abnormal activation/expression of both CARM1 and PRMT5.

Ribavirin inhibits colorectal cancer growth by downregulating PRMT5 expression and H3R8me2s and H4R3me2s accumulation.

Eukaryotic translation initiation factor 4E (eIF4E) and protein arginine methyltransferase 5 (PRMT5) are frequently overexpressed in colorectal cancer (CRC) tissues and associated with poor prognosis. Ribavirin, the only clinically approved drug known to target eIF4E, is an anti-viral molecule currently used in hepatitis C therapy. The potential of ribavirin to treat CRC remains largely unknown. Ribavirin treatment in CRC cell lines drastically inhibited cell proliferation and colony formation, induced S phase arrest and reduced cyclin D1, cyclin A/E and proliferating cell nuclear antigen (PCNA) levels in vitro, and suppressed tumorigenesis in mouse model of colitis-associated CRC. Mechanistically, ribavirin treatment significantly reduced PRMT5 and eIF4E protein levels and the accumulation of symmetric dimethylation of histone 3 at arginine 8 (H3R8me2s) and that of histone 4 at arginine 3 (H4R3me2s). Importantly, inhibition of PRMT5 by ribavirin resulted in promoted H3R8 methylation in eIF4E promoter region. Our results demonstrate the anti-cancer efficacy of ribavirin in CRC and suggest that the anti-cancer efficacy of ribavirin may be mediated by downregulating PRMT5 levels but not its enzymatic activity.

Antitumor activity of ginsenoside Rd in gastric cancer via up-regulation of Caspase-3 and Caspase-9.

Ginsenoside Rd (GS-Rd), isolated from the Chinese traditional herbal medicine Panax ginseng, is used for the treatment of cardiovascular diseases, inflammation, different body pains, and trauma. Caspase-3 and Caspase-9 belong to cysteine aspartic acid specific protease (Caspase) family that plays an important role in apoptosis progression of cancers. In the present study, we investigated the anti-tumor effect of GS-Rd by MTT assay, colony formation assessment, flow cytometry, and Western blotting. Our results revealed that ginsenoside Rd significantly inhibits human gastric cancer (GC) growth and cell proliferation. Flow cytometer analysis showed that the GS-Rd could significantly induce apoptosis and arrest the G0/G1 phase in GC cells. Further, GS-Rd was found to increase the ratio of Bax/Bcl-2 and the expression of Caspase-3 and Caspase-9, respectively, and to decrease the expression of Cyclin D1. Taken together, our study suggests that GS-Rd significantly inhibits GC cell proliferation, induces cell apoptosis through increase the expression of Caspase-3, Caspase-9, and the ratio of Bax/Bcl-2. GS-Rd also induces cell cycle arrest at G0/G1 phase by down-regulation Cyclin D1. Thus, GS-Rd could serve as a lead to develop novel therapeutic agents to against human gastric cancer.

Secreted clusterin inhibits tumorigenesis by modulating tumor cells and macrophages in human meningioma.

BACKGROUND: Meningioma is the most common primary intracranial tumor with a high frequency of postoperative recurrence, yet the biology of the meningioma malignancy process is still obscure. METHODS: To identify potential therapeutic targets and tumor suppressors, we performed single-cell transcriptome analysis through meningioma malignancy, which included 18 samples spanning normal meninges, benign and high-grade in situ tumors, and lung metastases, for extensive transcriptome characterization. Tumor suppressor candidate gene and molecular mechanism were functionally validated at the animal model and cellular levels. RESULTS: Comprehensive analysis and validation in mice and clinical cohorts indicated clusterin (CLU) had suppressive function for meningioma tumorigenesis and malignancy by inducing mitochondria damage and triggering type 1 interferon pathway dependent on its secreted isoform, and the inhibition effect was enhanced by TNFα as TNFα also induced type 1 interferon pathway. Meanwhile, both intra- and extracellular CLU overexpression enhanced macrophage polarization towards M1 phenotype and TNFα production, thus promoting tumor killing and phagocytosis. CONCLUSIONS: CLU might be a key brake of meningioma malignance by synchronously modulating tumor cells and their microenvironment. Our work provides comprehensive insights into meningioma malignancy and a potential therapeutic strategy.

Metabolomics study of ribavirin in the treatment of orthotopic lung cancer based on UPLC-Q-TOF/MS.

Ribavirin is a common antiviral drug, especially for patients with hepatitis C. Our recent studies demonstrated that ribavirin showed anti-tumor activity in colorectal cancer and hepatocellular carcinoma, but its effects on lung cancer remains unclear. This study aimed to evaluate the anti-tumor activity of ribavirin against lung cancer and elucidate the underlying mechanism. We established orthotopic mouse model of lung cancer (LLC and GLC-82) and employed an ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS)-based metabolomics approach. We found that ribavirin significantly inhibited the proliferation and colony formation of lung cancer cells. Tumor sizes of orthotopic lung cancer in ribavirin-treated groups were also significantly lower than those in control groups. Metabolomics analysis revealed that ribavirin mainly affected 5 metabolic pathways in orthotopic lung tumor models, taurine and hypotaurine metabolism, nicotinate and nicotinamide metabolism, linoleic acid metabolism, arginine biosynthesis and arachidonic acid metabolism. Furthermore, we identified 5 upregulated metabolites including ß-nicotinamide adenine dinucleotide (NAD+), nicotinamide (NAM), taurine, ornithine and citrulline, and 7 downregulated metabolites including 1-methylnicotinamide (MNAM), S-adenosyl-l-homocysteine (SAH), N1-Methyl-2-pyridone-5-carboxamide (2PY), homocysteine (Hcy), linoleic acid, arachidonic acid (AA) and argininosuccinic acid in ribavirin-treated groups. These results provide new insight into the anti-tumor mechanism of ribavirin for lung cancer.

Ribavirin inhibits cell proliferation and metastasis and prolongs survival in soft tissue sarcomas by downregulating both protein arginine methyltransferases 1 and 5.

Protein arginine methyltransferases 1 and 5 (PRMT1 and PRMT5) are frequently overexpressed in diverse types of cancers and correlate with poor prognosis, thus making these enzymes potential therapeutic targets. The aim of this study was to assess and elucidate the anti-tumour effect and epigenetic regulatory mechanism of ribavirin in soft tissue sarcomas (STS). We showed that ribavirin inhibited growth and metastasis and prolonged survival in animals bearing STS cells by downregulating the mRNA and protein levels of PRMT1/PRMT5 and attenuating the accumulation of asymmetric and symmetric di-methylation of arginine (ADMA and SDMA). Furthermore, ribavirin lowered the permeability of the peritoneum in KM mice bearing S180 ascites via decreasing the level of vascular endothelial growth factor (VEGF). Ribavirin was a potent inhibitor of cell proliferation and metastasis in STS cells through downregulation of both type I PRMT1 and type II PRMT5. Ribavirin could be used to enhance the efficacy of doxorubicin in STS allograft tumour models.

Cell metabolic profiling of colorectal cancer via 1H NMR.

BACKGROUND: Protein arginine methyltransferase 5 (PRMT5) belongs to a large family of protein arginine methyltransferases (PRMTs) that play essential role in gene transcription and regulate tumorigenesis. However, the role of PRMT5 in the regulation of cancer cell metabolism remains unclear. METHODS: Cell metabolomic analysis was performed on SW480 cells transfected with small interfering RNA (siRNA) specifically targeting PRMT5, followed by metabolomic pathway analysis. RESULTS: PRMT5 was overexpressed in colorectal cancer (CRC) tissues, and downregulation of PRMT5 suppressed CRC cell proliferation and the levels of PRMT5 and symmetric dimethylation of histone H3 (H3R8me2s). In addition, we found distinct differences in metabolite classification and function in PRMT5 knockdown SW480 cells compared to control SW480 cells. PRMT5 knockdown increased the levels of amino acids and carbohydrates, particularly related to the arginine metabolism such as glutamate, glutamine (Gln), proline, creatine, creatinine and phosphocreatine (PCr). CONCLUSIONS: These findings revealed a key role for PRMT5 as a regulator of CRC cell metabolism to mediate arginine methylation in CRC cells.