Abstract 1221: Sigma-2 receptor/progesterone receptor membrane component 1 is a potential therapeutic target that modulates expression of HER2 in gastric cancer cell lines

Abstract

Abstract Background: Gastric cancer (GC) is the third leading cause of death from cancer globally. Sigma-2 Receptor/Progesterone Receptor Membrane Component 1 (S2R/Pgrmc1) is a cytochrome-related protein and it is upregulated in multiple types of cancer. S2R/Pgrmc1 binds to several proteins including epidermal growth factor receptor 1 (EGFR) and regulates the EGFR signaling in lung and breast cancer cells, as we previously showed. Human Epidermal Growth Factor Receptor 2 (HER2), a member of EGFRs family, has been evaluated as a potential therapeutic target for GC due to an identified link between expression of HER2 and severity of GC. Several HER2 inhibitors are currently under investigation in Phase I and II clinical trials. Most of them inhibit ligand binding or kinase activity of HER2. Here, we suggest that HER2 is a novel molecular target of S2R/Pgrmc1, thus, inhibiting S2R/Pgrmc1 can be a potential therapeutic strategy for GC. Results: We found that the protein expression of S2R/Pgrmc1 is elevated in human gastric cancer tissue array and in multiple gastric cancer cell lines such as AGS, NCI-N87, and Hs 746T. Approximately 60% of GC cells have moderate to strong staining of S2R/Pgrmc1 as compared to weak staining noted in normal gastric cells, suggesting an association of S2R/Pgrmc1 with pathogenesis of GC. We also found that S2R/Pgrmc1 was inhibited by AG205, an inhibitor of PGRMC1, in concentration-dependent manner in NCI-N87 GC cell line. Consistently, AG205 inhibited proliferation of NCI-N87 cells in concentration- and time-dependent manner (p-value = 0.025). HER2 is a prognostic marker in GC and overexpression of protein level of HER2 is associated with tumor growth. We found that HER2 expression was decreased in AG205 treated NCI-N87 in concentration-dependent manner. Furthermore, we showed that AG205 enhanced the sensitivity of Herceptin, an anti-HER2 antibody that inhibits tumor growth. Akt, a downstream target of HER2, is overexpressed in GC, and regulates tumorigenic properties of cancer cells including tumor growth and survival. Here, we demonstrated that concomitant treatment of the GC cells with Herceptin and AG205 significantly decreased Akt protein level as compared to control cells or cell treated with Herceptin alone. Consistently, the viability of the cells was significantly lower in combination treatment group (p-value = 0.009), as compared to groups treated with Herceptin or AG205 alone. Conclusion: We have demonstrated that S2R/Pgrmc1 promotes proliferation of GC cell line and regulates the expression of HER2. Our results suggest that targeting S2RPgrmc1 could be a potential therapeutic target for gastric cancer. Citation Format: Balaqis Al Naamani, Maiya Al Bahri, Shadya Al-Sinawi, Ikhlas Ahmed. Sigma-2 receptor/progesterone receptor membrane component 1 is a potential therapeutic target that modulates expression of HER2 in gastric cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1221.