Poster abstracts
Poster number 38 submitted by Subhadeep Das
Unraveling the Role of DDX5 in Small Cell Lung Cancer
Subhadeep Das (Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA), Matt Russon (Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA), Maria P Zea Rojas (Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA), Bennett D. Elzey (Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana 47907, USA), Elizabeth Tran (Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA)
Abstract:
DDX5 is a DEAD-box RNA helicase that is overexpressed and implicated in playing roles in several cancers. One of these is small cell lung cancer (SCLC). SCLC is an extremely lethal, recalcitrant tumor, causing 250,000 deaths annually worldwide and currently lacking effective treatments. Supinoxin (RX 5902), a compound having anti-cancer activity, is a known target of phosphor-DDX5; Supinoxin blocks the interaction between beta-catenin and phosphor-DDX5, thereby releasing beta-catenin and allowing its degradation. In an effort to repurpose Supinoxin for treatment of SCLC, we conducted a series of in vitro and in vivo experiments. Supinoxin has been observed to impede the proliferation of H69AR cell lines, with an IC50 value of 63.2 ±18.5 (Mean ± SD). The colony formation of H69AR cells in soft agar was inhibited by 70 nM of Supinoxin. Supinoxin has the potential to mitigate both the growth of H69AR xenograft tumors and SCLC PDX tumors in vivo at a dosage of 70mg/kg in immunocompromised mice. The findings indicate that the administration of Supinoxin was effective in suppressing the growth of tumors and enhancing the survival rate of mice afflicted with SCLC tumors. Subsequently, an effort was made to explore the molecular pathways involved in the activity of Supinoxin in Small Cell Lung Cancer (SCLC) cells. Surprisingly, we did not see any decrease in beta-catenin levels or relocalization from the cytoplasm upon Supinoxin treatment. Moreover, we did not observe any decrease in the expression levels of beta-catenin target genes thereby contradicting the current model. Based on the data obtained from our laboratory we found that the current model of Supinoxin activity is not accurate. We are now investigating differential gene expression (RNA-seq) in SCLC cell lines with and without Supinoxin in order to investigate potential possible paths via which Supinoxin operates on SCLC.
References:
1. Kost, G. C. et al. A Novel Anti-Cancer Agent, 1-(3,5-Dimethoxyphenyl)-4-[(6-Fluoro-2-Methoxyquinoxalin-3-yl)Aminocarbonyl] Piperazine (RX-5902), Interferes with β-Catenin Function Through Y593 Phospho-p68 RNA Helicase. J. Cell. Biochem. 116, 1595–1601 (2015).
2. Xing, Z., Russon, M. P., Utturkar, S. M. & Tran, E. J. The RNA helicase DDX5 supports mitochondrial function in small cell lung cancer. J. Biol. Chem. 295, (2020).
3. Capasso, A. et al. First-in-Class Phosphorylated-p68 Inhibitor RX-5902 Inhibits β-Catenin Signaling and Demonstrates Antitumor Activity in Triple-Negative Breast Cancer. Mol. Cancer Ther. (2019). doi:10.1158/1535-7163.mct-18-1334 (660 characters).
Keywords: Small Cell Lung Cancer, DDX5, Supinoxin