Microtubules and their role in cellular stress in cancer

Abstract

Microtubules are highly dynamic structures, which consist of α- and β-tubulin heterodimers, and are involved in cell movement, intracellular trafficking, and mitosis. In the context of cancer, the tubulin family of proteins is recognized as the target of the tubulin-binding chemotherapeutics, which suppress the dynamics of the mitotic spindle to cause mitotic arrest and cell death. Importantly, changes in microtubule stability and the expression of different tubulin isotypes as well as altered post-translational modifications have been reported for a range of cancers. These changes have been correlated with poor prognosis and chemotherapy resistance in solid and hematological cancers. However, the mechanisms underlying these observations have remained poorly understood. Emerging evidence suggests that tubulins and microtubule-associated proteins may play a role in a range of cellular stress responses, thus conferring survival advantage to cancer cells. This review will focus on the importance of the microtubule-protein network in regulating critical cellular processes in response to stress. Understanding the role of microtubules in this context may offer novel therapeutic approaches for the treatment of cancer.

Keywords: microtubule-associated proteins; microtubules; post-translational modifications; stress response; tubulin.

Figure 1

Microtubules are dynamic structures that interact with diverse proteins. (A) Microtubules form a dynamic network and are constantly lengthening and shortening. In interphase [(A), left], microtubules are anchored at the centrosome (minus end) and radiate toward the cell periphery (plus end). The microtubule network undergoes dramatic remodeling throughout the cell cycle, from interphase and through mitosis [(A), right]. Green: α-tubulin, blue: DAPI. Images courtesy of Dr. Sela Po’uha. (B) Heterodimers of α- and β-tubulin associate to form microtubules. The dynamic addition and removal of tubulin heterodimers is faster at microtubule plus ends than at microtubule minus ends. Both endogenous factors and TBAs regulate and influence microtubule dynamics. A variety of proteins involved in cellular homeostatic mechanisms and stress responses also interact with tubulins either in their soluble or polymerized forms. Post-translational modifications on tubulins influence these interactions. Adapted with permission from Macmillan Publishers Ltd: Nature Reviews Molecular Cell Biology [Ref. (9)], Copyright 2011 and Nature Reviews Cancer [Ref. (15)], Copyright 2010.

Figure 2

Microtubules regulate and co-ordinate diverse cellular stress responses in cancer cells. Alterations in the expression of tubulin isotypes, tubulin post-translational modifications, and the interaction of microtubules with MAPs seen in cancer affect a wide range of homeostatic mechanisms in response to cellular stress. Microtubules may function to co-ordinate stress responses across the cell, resulting in enhanced cell survival in the harsh tumor microenvironment, resistance to chemotherapy treatment, and the development of more aggressive disease; MT, microtubules.