Supinoxin Blocks Small Cell Lung Cancer Progression by Inhibiting Mitochondrial Respiration through DDX5. Supinoxin Blocks Small Cell Lung Cancer Progression by Inhibiting Mitochondrial Respiration through DDX5

DDX5 is a DEAD-box RNA helicase that is overexpressed and implicated in the progression of several cancers, including small cell lung cancer (SCLC). Our laboratory has demonstrated that DDX5 is essential for the invasive growth of SCLC and mitochondrial respiration. SCLC is an extremely lethal, recalcitrant tumor, and currently lacking effective treatments. Supinoxin (RX 5902), a compound having anti-cancer activity, is a known target of phosphor-DDX5. We now report that Supinoxin inhibits the proliferation of chemo-sensitive and chemo-resistant SCLC lines, H69 and H69AR respectively. Additionally, Supinoxin mitigates both the growth of H69AR xenograft tumors and SCLC PDX tumors in vivo. Finally, we find that Supinoxin inhibits expression of mitochondrial genes and effectively blocks respiration. These studies suggest that Supinoxin functions in anti-tumor progression by reducing cellular energy levels through DDX5. Overall design: To investigate the molecular pathway through which Supinoxin works on SCLC, we conducted differential gene expression in H69AR chemoresistant SCLC cells with or without 70 nM of Supinoxin.

DDX5是一种DEAD-box RNA解旋酶（DEAD-box RNA helicase），在包括小细胞肺癌（small cell lung cancer, SCLC）在内的多种癌症中呈高表达状态，且参与癌症的进展过程。本课题组已证实，DDX5对于小细胞肺癌的侵袭性生长以及线粒体呼吸功能不可或缺。小细胞肺癌是一类致死率极高、难治性极强的恶性肿瘤，目前尚无有效的临床治疗手段。Supinoxin（RX 5902）是一种具备抗癌活性的化合物，已被证实为磷酸化DDX5的已知靶点。本研究此次发现，Supinoxin可分别抑制化疗敏感型与化疗耐药型小细胞肺癌细胞系H69和H69AR的增殖。此外，Supinoxin在体内可抑制H69AR异种移植瘤以及小细胞肺癌患者来源异种移植（patient-derived xenograft, PDX）肿瘤的生长。最后本研究发现，Supinoxin可抑制线粒体基因的表达，并有效阻断细胞呼吸过程。上述研究表明，Supinoxin可通过DDX5降低细胞能量水平，从而发挥抗肿瘤进展的作用。整体实验设计：为探究Supinoxin作用于小细胞肺癌的分子通路，本研究对经70 nM Supinoxin处理与未处理的化疗耐药型小细胞肺癌H69AR细胞进行了差异基因表达分析。