Hypoxia induces microtubule rearrangement in intestinal epithelial cells

Microtubules are integral components of the highly regulated and dynamic cytoskeleton which is vital for cell function and the maintenance of homeostasis. Microtubule disruption is associated with multiple disease states including colorectal cancer and neurodegenerative disorders. While much is known about the mechanisms by which microtubules are regulated under physiologic conditions, the effect of pathological stimuli and how this contributes to disease progression is less clear. Hypoxia is a prominent microenvironmental feature of a range of pathological states including inflammation, ischemia, neurodegenerative disease, and cancer. However, our knowledge on the effect of hypoxia on microtubules and whether this impacts disease progression remains limited. Understanding the impact of hypoxia on microtubules is therefore of fundamental importance to understanding disease progression mediated by cytoskeletal changes and may identify new therapeutic targets. In this study, we found that hypoxia decreases intestinal epithelial cell migration. This is associated with a rapid and reversible change in microtubule structure. This cytoskeletal rearrangement occurs independently of changes in α-tubulin protein expression or free to polymerised α-tubulin ratio and is also independent of the hypoxia-inducible factor 1α (HIF-1α) pathway. Mechanistically we found that it is hypoxia-induced changes in glycolytic metabolism that mediate the structural rearrangement of α-tubulin. We hypothesise that these data identify a potential opportunity to utilise drugs targeting glycolytic metabolism to sensitise drug-resistant colorectal epithelial cancer cells to microtubule-based chemotherapies.