Supinoxin blocks Small Cell Lung Cancer Progression by Inhibiting Mitochondrial Respiration through the RNA Helicase DDX5.

DDX5 is a DEAD-box RNA helicase that is overexpressed and implicated in progression of several cancers 1-4 . One of these is small cell lung cancer (SCLC). Our laboratory has demonstrated that the RNA helicase DDX5 is essential for the invasive growth of SCLC and mitochondrial respiration 5 . SCLC is an extremely lethal, recalcitrant tumor 6,7 , causing 250,000 deaths annually worldwide 8 and currently lacking effective treatments 9,10 . Supinoxin (RX 5902), a compound having anti-cancer activity 11 , is a known target of phosphor-DDX5 12,13 ; Supinoxin blocks the interaction between β-catenin and phosphor-DDX5 13 , thereby releasing β-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. Additionally, 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 is effective in suppressing the growth of tumors and enhancing the survival rate of mice 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 β-catenin levels or relocalization from the cytoplasm upon Supinoxin treatment. Moreover, we did not observe any decrease in the expression levels of β-catenin target genes thereby contradicting the current model. Based on our current data we found that the current model of Supinoxin activity is inaccurate. Additional investigations were conducted to explore the mechanisms by which Supinoxin affects small cell lung cancer (SCLC). Treatment with Supinoxin induced mitochondrial dysfunction in the chemoresistant small cell lung cancer (SCLC) cell line H69AR. The latter was evidenced by down-regulation of genes associated with oxidative phosphorylation. Thus, Supinoxin is a new therapeutic agent for small cell lung cancer (SCLC).