Non-small cell lung cancer (NSCLC) survival rates are dismal and high βIII-tubulin expression is associated with chemotherapy drug resistance and tumor aggressiveness in this disease. Mounting evidence supports a role for βIII-tubulin in promoting cell survival in the harsh tumor microenvironment, which is characterized by poor nutrient supply. This study aimed to investigate the role of βIII-tubulin in glucose stress response signaling and the survival and proliferation of NSCLC cells. This study revealed that βIII-tubulin regulates cellular metabolism and glucose stress response signaling in NSCLC cells to promote cell survival and proliferation in glucose starvation. βIII-Tubulin decreases the reliance of cells on glycolytic metabolism, priming them to cope with variable nutrient supply present within the tumor microenvironment. βIII-Tubulin protects cells from endoplasmic reticulum (ER) stress and reduces both basal and glucose starvation-induced autophagy to maintain cell survival and proliferation. βIII-Tubulin enables rapid Akt activation in response to glucose starvation and co-immunoprecipitates with the master regulator of the ER stress response GRP78. Furthermore, suppression of βIII-tubulin delays the association of GRP78 with Akt in response to glucose starvation with the potential to influence Akt activation and ER homeostasis under these conditions. Together these results identify that βIII-tubulin regulates glucose metabolism and alters glucose starvation stress signaling to promote cell proliferation and survival in NSCLC cells. This elucidates a hitherto unknown role for this microtubule protein and provides insight into correlations between high βIII-tubulin expression and poor patient outcome in this disease.
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