Abstract
Tubulin proteins, as components of the microtubule cytoskeleton perform critical cellular functions throughout all phases of the cell cycle. Altered tubulin isotype composition of microtubules is emerging as a feature of aggressive and treatment refractory cancers. Emerging evidence highlighting a role for tubulin isotypes in differentially influencing microtubule behaviour and broader functional networks within cells is illuminating a complex role for tubulin isotypes regulating cancer biology and chemotherapy resistance. This review focuses on the role of different tubulin isotypes in microtubule dynamics as well as in oncogenic changes that provide a survival or proliferative advantage to cancer cells within the tumour microenvironment and during metastatic processes. Consideration of the role of tubulin isotypes beyond their structural function will be essential to improving the current clinical use of tubulin-targeted chemotherapy agents and informing the development of more effective cancer therapies.
Highlights
The microtubule cytoskeleton is an extensive network of filaments that span the cell interior
The dynamics of tubulin heterodimer addition and release are slower at the minus end of the microtubule, which terminates in α-tubulin proteins, compared with the plus end of the microtubule, which terminates with β-tubulin proteins capped in the GTP-bound state [2,3]
This review focuses on the current knowledge of the role of tubulin isotypes in chemotherapy drug resistance, disease aggressiveness and tumour biology
Summary
The microtubule cytoskeleton is an extensive network of filaments that span the cell interior. Microtubules are composed of αβ-tubulin heterodimers that associate to form protofilaments, which laterally associate to form microtubules [1] These highly dynamic structures are constantly lengthening and shortening throughout all phases of the cell cycle by the addition and removal of tubulin heterodimers at the microtubule ends. The N-terminal and intermediate domains of the protein form a highly conserved and rigid globular tubulin body that stack to form protofilaments, while the C-terminal tail of the protein is a highly disordered peptide 18–24 amino acids in length These C-terminal tails are sites for post-translational modifications and mediate interactions with a range of proteins [4], which collectively impart unique functionality to each tubulin isotype [4]. Α-tubulin isotypes, similar to β-tubulin isotypes, will be increasingly associated with cancer patient outcome with further advances in our understanding of tubulin and tumour biology
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