Project description:Microtubule-targeting agents have been widely used for cancer treatment, yet their cancer specificity is a common challenge. In this study, we identified that CMPD1 as a promising cancer specific inhibitor. Both in vitro and in vivo experiments showed that CMPD1 efficiently inhibits tumor growth. Mechanistically, CMPD1 inhibits microtubule polymerization in mitosis. Collectively, CMPD1 has the high potential to serve as a cancer cell inhibitor.
Project description:Endocrine therapy is the most important treatment modality of breast cancer patients whose tumors express the estrogen receptor (ER). The androgen receptor (AR) is also expressed in the vast majority (80-90%) of ER-positive tumors. However, AR-targeting drugs are not used in clinical practice, but have been evaluated in multiple trials and preclinical studies. We performed a genome-wide study to identify genetic context-dependent AR signaling induced by either AR agonist (dihydrotestosterone [DHT]), or AR antagonist (enzalutamide [Enz]), known as pharmacogenomic expression quantitative expression loci (PGx-eQTLs), utilizing a previously well characterized lymphoblastic cell line panel.
Project description:Search for SNPs associated with the pharmacogenomic profile of Benzidazole adverse reactions in Chagas Disease Homo sapiens patients.
Project description:This study is a comparative analysis to examine whether there are significant gene expression changes after 6 hours of treatment with three diverse microtubule destabilizers: combretastation A4 (CA4), vinblastine (VB), and plinabulin (PL). Other comparators include baseline control DMSO, microtubule destabilizer docetaxel (DTXL), and inflammatory cytokine TNF-α. We use primary human pulmonary microvascular endothelial cells as a model for a cell sensitive to microtubule perturbations.
Project description:Circular RNAs (circRNAs) are widely expressed in eukaryotes and highly regulated in a myriad of biological processes. While many studies indicate their activity as miRNA and protein sponges, little is known about their ability to directly control mRNA homeostasis. We show that a widely expressed circRNA, circZNF609, directly interacts with several mRNAs and increases their stability and/or translation by favouring the recruitment of the RNA-binding protein ELAVL1. Specifically, the interaction with Ckap5 mRNA, that interestingly overlaps the back-splicing junction, regulates microtubule homeostasis in several cancer cell lines and sustains cell-cycle progression. Finally, we show that circZNF609 downregulation increases the sensitivity to several microtubule-targeting cancer drugs in the regulation of microtubule metabolism and that LNA protectors against the Ckap5 pairing region on circZNF609 phenocopies such activity. These data set an example of how the small effects tuned by circZNF609/Ckap5 mRNA interaction might have potent output in tumour growth and drug response.
Project description:MI-773 is a recently developed small-molecule inhibitor of the Mouse Double Minute 2 (MDM2) proto-oncogene. Here we report an integrative pharmacogenomic study to gain further insights into the therapeutic potential of the compound.
Project description:At the cellular level, α-tubulin acetylation alters the structure of microtubules to render them mechanically resistant to compressive forces. How this biochemical property of microtubule acetylation relates to mechanosensation remains unknown, though prior studies have shown that microtubule acetylation influences touch perception. Here, we identify the major Drosophila α-tubulin acetylase (dTAT) and show that it plays key roles in several forms of mechanosensation. dTAT is highly expressed in the larval peripheral nervous system (PNS), but is largely dispensable for neuronal morphogenesis. Mutation of the acetylase gene or the K40 acetylation site in α-tubulin impairs mechanical sensitivity in sensory neurons and behavioral responses to gentle touch, harsh touch, gravity, and vibration stimuli, but not noxious thermal stimulus. Finally, we show that dTAT is required for mechanically-induced activation of NOMPC, a microtubule-associated transient receptor potential channel, and functions to maintain integrity of the microtubule cytoskeleton in response to mechanical stimulation.