Class III beta-tubulin, drug resistance and therapeutic approaches in cancers

Abstract

Class III beta-tubulin is one of the critical proteins associated with microtubule assembly, important to many cellular functions including mitochondrial respiration and intracellular trafficking. Widely regarded as a specific neuronal marker in developmental neurobiology and stem cell research, it is also highly expressed in a wide range of tumors of both neuronal and non-neuronal origin. The expression of class III beta-tubulin is tightly controlled at multiple levels with tissue-dependent mechanisms of regulation. For instance, class III beta-tubulin expression is under the control of estrogens in breast cancer cells but is influenced by exposure to hypoxia and poor-nutrient supply in ovarian cancer. In some but not all cancers, class III beta-tubulin expression is purely a prognostic biomarker, predicting poor outcome of patients regardless of chemotherapy treatment. Moreover, the expression of class III beta-tubulin does not confer an aggressive phenotype by itself. Instead, class III beta-tubulin functions like a cytoskeletal gateway, which enhances the incorporation of pro-survival kinases into the cytoskeleton and protects them from degradation. The associations of class III beta-tubulin with survival kinase PIM-1, RNA-binding protein HuR, microRNAs are examples highlighting the functional complexity of this protein. The utility of class III beta-tubulin as a prognostic biomarker can also greatly improve if combined with these pro-survival partners. Subsequently, pharmacogenetic approaches, designed to counteract and target these pathways and associated-factors concurrently, might lead to better therapies and prognostic tools for class III beta-tubulin expressing cancers.