ver-155008 and Colorectal-Neoplasms

Colorectal cancer (CRC) is one of the most common malignancies in the world. Despite intensive advances in diagnosis and treatment of CRC, it is yet one of the leading cause of cancer related morbidity and mortality. Therefore, there is an urgent medical need for alternative therapeutic approaches to treat CRC. The 70 kDa heat shock proteins (Hsp70s) are a family of evolutionary conserved heat shock proteins, which play an important role in cell homeostasis and survival. They overexpress in various types of malignancy including CRC and are typically accompanied with poor prognosis. Hence, inhibition of Hsp70 may be considered as a striking chemotherapeutic avenue. This review summarizes the current knowledge on the progress made so far to discover compounds, which target the Hsp70 family, with particular emphasis on their efficacy in treatment of CRC. We also briefly explain the induction of Hsp70 as a strategy to prevent CRC.

Topics: Antineoplastic Agents; Biological Products; Carbamates; Colorectal Neoplasms; Endoplasmic Reticulum Chaperone BiP; Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Molecular Targeted Therapy; Purine Nucleosides; Pyrimidinones

Amino-terminal enhancer of split (Aes) is a member of Groucho/Transducin-like enhancer (TLE) family. Aes is a recently found metastasis suppressor of colorectal cancer (CRC) that inhibits Notch signalling, and forms nuclear foci together with TLE1. Although some Notch-associated proteins are known to form subnuclear bodies, little is known regarding the dynamics or functions of these structures. Here, we show that Aes nuclear foci in CRC observed under an electron microscope are in a rather amorphous structure, lacking surrounding membrane. Investigation of their behaviour during the cell cycle by time-lapse cinematography showed that Aes nuclear foci dissolve during mitosis and reassemble after completion of cytokinesis. We have also found that heat shock cognate 70 (HSC70) is an essential component of Aes foci. Pharmacological inhibition of the HSC70 ATPase activity with VER155008 reduces Aes focus formation. These results provide insight into the understanding of Aes-mediated inhibition of Notch signalling.

Topics: Adenosine Triphosphatases; Animals; Cell Nucleus; Co-Repressor Proteins; Colorectal Neoplasms; Cytokinesis; HCT116 Cells; HEK293 Cells; HSC70 Heat-Shock Proteins; Humans; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Microscopy, Immunoelectron; Mitosis; Purine Nucleosides; Receptors, Notch; Repressor Proteins; Signal Transduction; Time-Lapse Imaging