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Lung cancer is the most common malignancy worldwide and is a focus for developing targeted therapies due to its refractory nature to current treatment. We identified a RNA helicase, DDX3, which is overexpressed in many cancer types including lung cancer and is associated with lower survival in lung cancer patients. We designed a first-in-class small molecule inhibitor, RK-33, which binds to DDX3 and abrogates its activity. Inhibition of DDX3 by RK-33 caused G1 cell cycle arrest, induced apoptosis, and promoted radiation sensitization in DDX3-overexpressing cells. Importantly, RK-33 in combination with radiation induced tumor regression in multiple mouse models of lung cancer. Mechanistically, loss of DDX3 function either by sh RNA or by RK-33 impaired Wnt signaling through disruption of the DDX3-β-catenin axis and inhibited non-homologous end joining-the major DNA repair pathway in mammalian somatic cells. Overall, inhibition of DDX3 by RK-33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for lung cancer therapy. [ABSTRACT FROM AUTHOR]

Altered choline phospholipid metabolism is a hallmark of cancer, leading to malignant choline metabolite profiles consisting of low glycerophosphocholine (GPC) and high phosphocholine (PC) in human breast cancers. Glycerophosphocholine phosphodiesterase (GPC-PDE) catalyzes the degradation of GPC to free choline and glycerol-3-phosphate. The gene(s) encoding for the GPC-PDE(s) responsible for GPC degradation in breast cancers have not yet been identified. Here, we demonstrate for the first time that the GPC-PDE encoded by glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) is associated with breast cancer malignancy. Two human breast cancer cell lines ( n = 8 and n = 10) and primary human breast tumor samples ( n = 19) were studied with combined MRS and quantitative reverse transcription-polymerase chain reaction to investigate several isoforms of GDPD expression with respect to choline phospholipid metabolite levels. Of the five GDPDs tested, GDPD5 was found to be significantly overexpressed in highly malignant estrogen receptor negative (ER-) compared with weakly malignant estrogen receptor positive (ER+) human breast cancer cells ( p = 0.027) and breast tumors from patients ( p = 0.015). GDPD5 showed significantly positive correlations with PC ( p < 0.001), total choline (tCho) ( p = 0.007) and PC/GPC ( p < 0.001) levels in human breast tumors. GDPD5 showed a trend towards a negative correlation with GPC levels ( p = 0.130). Human breast cancers with malignant choline metabolite profiles consisting of low GPC and high PC levels highly co-expressed GDPD5, choline kinase alpha (CHKA) and phosphatidylcholine-specific phospholipase D1 (PLD1), whereas cancers containing high GPC and relatively low PC levels displayed low co-expression of GDPD5, CHKA and PLD1. GDPD5, CHKA and PLD1 were significantly overexpressed in highly malignant ER- tumors in our patient cohort. Our study identified GDPD5 as a GPC-PDE that probably participates in the regulation of choline phospholipid metabolism in breast cancer, which possibly occurs in cooperation with CHKA and PLD1. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]