Background: Ovarian cancer is the most common lethal cancer of the female reproductive system and is often diagnosed in advanced stages. The Sortilin 1 (SORT1) gene is overexpressed in ovarian cancer cells. Methyl protodioscin, an herbal bioactive compound, has significant antitumor activities. Objectives: Considering the necessity of identifying new medicinal agents and treatments in ovarian cancer, this project investigated the effects of methyl protodioscin on the expression of the SORT1 gene and the response to chemotherapy in the ovarian cancer cell line (A2780 S). Methods: The viability of ovarian cancer cells (A2780) after treatment with methyl protodioscin (800, 400, 200, 100, 50, 25, 12.5, 6.25, and 3.12 µM) was evaluated by MTT assay, trypan blue staining, and lactate dehydrogenase activity measurement. The expression level of the SORT1 gene was investigated by real-time PCR. The effect of simultaneous treatment with methyl protodioscin and the chemotherapy drug carboplatin on cell viability was measured.Results: After 24, 48, 72, and 96 hours of treatment, methyl protodioscin significantly decreased cell viability in a concentration- and time-dependent manner (P < 0.05). After 24 hours, treatment with the IC50 concentration of methyl protodioscin (14.5 µM) caused a significant decrease in SORT1 expression in ovarian cancer cells by 33% (P < 0.05). The combination of methyl protodioscin with carboplatin decreased cell viability with a synergistic effect.Conclusions: Methyl protodioscin had an inhibitory effect on the survival of ovarian cancer cells in a concentration- and time-dependent manner and reduced the expression of the SORT1 gene. Additionally, this herbal compound synergistically increased the toxicity of carboplatin.

Introduction: Ovarian cancer is one of the deadliest genital cancers among females and mainly originates from epithelial cells. The cancer generally remains asymptomatic until metastasis. Silibinin, a derivative of Silybum marianum, is a flavonoid with anticancer effects against many tumor cells. The sortilin1 (SORT1) gene has been shown to be overexpressed in ovarian tumors. Here, we investigated the effects of silibinin on SORT1 gene expression and the viability of ovarian A2780s cancer cell line. Methods: The A2780s ovarian cancer cell line was treated with silibinin at the concentrations of 50, 100, and 200 μ, M for 24 hours, and IC50 (half-maximal inhibitory concentration) was determined. Then the viability percentage of the cells treated with 100 μ, M silibinin was determined at 24, 48, and 72 hours. After 24 and 48 hours exposure to 100 μ, M silibinin, RNA was extracted, followed by cDNA synthesis and SORT1 gene expression analysis using glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as the reference gene by real-time Polymerase chain reaction (PCR). Results: Silibinin in a dose-and time-dependent manner reduced the viability of ovarian cancer cells (P < 0. 05), accompanied by a reduction in SORT1 gene expression. Conclusion: The present study showed that silibinin had toxic effects against the A2780s ovarian cancer cell line, suggesting this compound as a potential anticancer agent.

Introduction: Hepatitis B virus (HBV) infection is a major global health problem. Chronically infected people are at risk for progressive hepatic fibrosis and consequent cirrhosis. Hepatitis B surface antigen (HBsAg) level in serum is a complementary marker for intrahepatic HBV DNA and covalently closed circular DNA (cccDNA). Sortilin-1 (SORT1) has been reported to be involved in the post-Golgi vesicle trafficking of Apo lipoproteins degradation pathways. This study was designed to evaluate the hepatic and serum expression of HBsAg and its association with hepatic SORT1 gene expression in patients with chronic HBV.Methods: Thirty chronic hepatitis B patients with histological examination results were enrolled in this study. Liver biopsies were analyzed for hepatic HBsAg and SORT1 gene expression by immunohistochemistry and quantitative real time PCR (qRT-PCR), respectively.Results: Twenty seven out of 30 (90%) liver biopsies had positive staining for HBsAg and showed a significant inverse association with hepatic SORT1 fold change gene expression (b=-0.5, P=0.042).There was significant association between HBV DNA levels and HBsAg expression in hepatocyte or serum titer of HBsAg (r=0.39, P=0.029; r=0.39, P=0.032respectively). Serum ALT was also correlated with hepatic activity index (HAI) score (b=0.6, P=0.001).Conclusion: Inverse association between hepatic SORT1 gene expression and hepatic HBsAg expression indicates the possible role of sortilin in HBsAg particle formation.

Background: Our preliminary data on the protein expression of SORT1 in ovarian carcinoma tissues showed that sortilin was overexpressed in ovarian carcinoma patients and cell lines, while non-malignant ovaries expressed comparably lower amount of this protein. In spite of diverse ligands and also different putative functions of sortilin (NTR3), the function of overexpressed sortilin in ovarian carcinoma cells is an intriguing subject of inquiry. The aim of this study was, therefore, to investigate the functional role of sortilin in survival of ovarian carcinoma cell line.Methods: Expression of sortilin was knocked down using RNAi technology in the ovarian carcinoma cell line, Caov-4. Silencing of SORT1 expression was assessed using real-time qPCR and Western blot analyses. Apoptosis induction was evaluated using flow cytometry by considering annexin-V FITC binding. [3H]-thymidine incorporation assay was also used to evaluate cell proliferation capacity.Results: Real-time qPCR and Western blot analyses showed that expression of sortilin was reduced by nearly 70-80% in the siRNA transfected cells. Knocking down of sortilin expression resulted in increased apoptosis (27.5±0.48%) in siRNA-treated ovarian carcinoma cell line. Sortilin silencing led to significant inhibition of proliferation (40.1%) in siRNA-transfected Caov-4 cells as compared (p<0.05).Conclusion: As it was suspected from overexpression of sortilin in ovarian tumor cells, a cell survival role for sortilin can be deduced from these results. In conclusion, the potency of apoptosis induction via silencing of sortilin expression in tumor cells may introduce sortilin as a potential candidate for developing a novel targeted therapy in patients with ovarian carcinoma to mock control-transfected counterpart.

Gene expression profiling of ovarian carcinoma tissues has shown an increase of four-fold expression of SORT1 gene. Sortilin 1 (NTR-3) is a 95-100 kDa protein normally expressed in heart, brain, placenta, skeletal muscle, spinal cord, thyroid, and testis. However, its expression has never been reported in normal ovary. Here, we report expression of sortilin 1 in ovarian carcinoma tissues both at gene and protein levels. Sortilin 1 was expressed in all ovarian carcinoma patients (n=15) as well as ovarian carcinoma cell lines (n=5) regardless of their phenotypic characteristics. Non-malignant ovaries (n=6) did not express sortilin 1. The molecular basis for this ectopic expression is not yet clear. Our results showed a major cell surface expression of sortilin 1 rather than ER-Golgi compartment where it is mainly expressed. This finding may introduce sortilin 1 as a novel tumor marker for diagnosis of ovarian carcinoma and may signify its therapeutic value in targeted therapy.