on-01910 and Cell-Transformation--Neoplastic

Prostate cancer (PCa) is the most commonly occurring cancer in American men, next to skin cancer. Existing treatment options and surgical intervention are unable to effectively manage this cancer. Therefore, continuing efforts are ongoing to establish novel mechanism-based targets and strategies for its management. The serine/threonine kinases Polo-like kinase (Plk) 1 plays a key role in mitotic entry of proliferating cells and regulates many aspects of mitosis which are necessary for successful cytokinesis. Plk1 is over-expressed in many tumor types with aberrant elevation frequently constituting a prognostic indicator of poor disease outcome. This review discusses the studies which indicate that Plk1 could be an excellent target for the treatment as well as chemoprevention of prostate cancer.

Topics: Animals; Antibodies; Antineoplastic Agents; Cell Cycle Proteins; Cell Line, Tumor; Cell Transformation, Neoplastic; Chemoprevention; Female; Glycine; Humans; Male; Mice; Mitosis; NIH 3T3 Cells; Polo-Like Kinase 1; Prostatic Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Sulfones

Oncogenic activation of RAS genes via point mutations occurs in 20%-30% of human cancers. The development of effective RAS inhibitors has been challenging, necessitating new approaches to inhibit this oncogenic protein. Functional studies have shown that the switch region of RAS interacts with a large number of effector proteins containing a common RAS-binding domain (RBD). Because RBD-mediated interactions are essential for RAS signaling, blocking RBD association with small molecules constitutes an attractive therapeutic approach. Here, we present evidence that rigosertib, a styryl-benzyl sulfone, acts as a RAS-mimetic and interacts with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway. We also find that ribosertib binds to the RBDs of Ral-GDS and PI3Ks. These results suggest that targeting of RBDs across multiple signaling pathways by rigosertib may represent an effective strategy for inactivation of RAS signaling.

Topics: Amino Acid Sequence; Animals; Cell Cycle Proteins; Cell Transformation, Neoplastic; Crystallography, X-Ray; Dimerization; Glycine; Humans; MAP Kinase Signaling System; Mice; Mice, Nude; Models, Molecular; Molecular Sequence Data; Nuclear Magnetic Resonance, Biomolecular; Pancreatic Neoplasms; Phosphorylation; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; ras Proteins; RNA-Binding Proteins; Sequence Alignment; Signal Transduction; Sulfones