Chemical Biology Drug Sensitivity Screen Identifies Sunitinib as Synergistic Agent with Disulfiram in Prostate Cancer Cells

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Stemness and plasticity of lung cancer cells: paving the road for better therapy

Judong Luo,1,2,* Xifa Zhou,1,* Juan Sebastian Yakisich3 1Changzhou Tumor Hospital, Soochow University, Changzhou, 2School of Radiation Medicine and Protection, Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, People's Republic of China;  3Department of Clinical Neuroscience, Karolinska University Hospital Stockholm, Sweden*These authors contributed equally to this work.Abstract: Lung cancer is a devastating disease that is responsible for around 160,000 deaths each year in United States. The discovery that lung cancer, like most other solid tumors, contains a subpopulation of cancer stem cells or cancer stem-like cells (CSCs/CS-LCs) that if eliminated could lead to a cure has brought new hope. However, the exact nature of the putative lung CSCs/CS-LCs is not known and therefore therapies to eliminate this subpopulation have been elusive. A limited knowledge and understanding of cancer stem cell properties and tumor biology may be responsible for the limited clinical success. In this review we discuss the stemness and plasticity properties of lung cancer cells that are critical aspects in terms of developing effective therapies. We suggest that the available experimental evidence obtained from lung cancer cell lines and patients' derived primary cultures does not support a tumor model consistent with the classical CSC model. Instead, all lung cancer cells may be extremely versatile and new models of cancer stem cells may be better working models.Keywords: cancer stem cells, chemotherapy, interconversion, plasticity, phenotyp

Genome-Wide Analysis of the Phosphoinositide Kinome from Two Ciliates Reveals Novel Evolutionary Links for Phosphoinositide Kinases in Eukaryotic Cells

Background: The complexity of phosphoinositide signaling in higher eukaryotes is partly due to expansion of specific families and types of phosphoinositide kinases (PIKs) that can generate all phosphoinositides via multiple routes. This is particularly evident in the PI3Ks and PIPKs, and it is considered an evolutionary trait associated with metazoan diversification. Yet, there are limited comprehensive studies on the PIK repertoire of free living unicellular organisms. Methodology/Principal Findings: We undertook a genome-wide analysis of putative PIK genes in two free living ciliated cells, Tetrahymena and Paramecium. The Tetrahymena thermophila and Paramecium tetraurelia genomes were probed with representative kinases from all families and types. Putative homologs were verified by EST, microarray and deep RNA sequencing database searches and further characterized for domain structure, catalytic efficiency, expression patterns and phylogenetic relationships. In total, we identified and characterized 22 genes in the Tetrahymena thermophila genome and 62 highly homologues genes in Paramecium tetraurelia suggesting a tight evolutionary conservation in the ciliate lineage. Comparison to the kinome of fungi reveals a significant expansion of PIK genes in ciliates. Conclusions/Significance: Our study highlights four important aspects concerning ciliate and other unicellular PIKs. First, ciliate-specific expansion of PI4KIII-like genes. Second, presence of class I PI3Ks which, at least in Tetrahymena, are associated with a metazoan-type machinery for PIP3 signaling. Third, expansion of divergent PIPK enzymes such as the recently described type IV transmembrane PIPKs. Fourth, presence of possible type II PIPKs and presumably inactive PIKs (hence, pseudo-PIKs) not previously described. Taken together, our results provide a solid framework for future investigation of the roles of PIKs in ciliates and indicate that novel functions and novel regulatory pathways of phosphoinositides may be more widespread than previously thought in unicellular organisms