title: βIII-Tubulin alters glucose metabolism and stress response signaling to promote cell survival and proliferation in glucose-starved non-small cell lung cancer cells.
abstract: 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.
authors.affiliation: Tumour Biology and Targeting Program, Children's Cancer Institute, UNSW Lowy Cancer Research Centre, Randwick, NSW 2031, Australia.|Australian Centre for Nanomedicine and ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, UNSW Australia, Sydney, NSW 2052, Australia and.
authors.forename: Amelia L
authors.initials: AL
authors.lastname: Parker
authors.affiliation: Department of Pharmacology, School of Medical Sciences, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Nigel
authors.initials: N
authors.lastname: Turner
authors.affiliation: Tumour Biology and Targeting Program, Children's Cancer Institute, UNSW Lowy Cancer Research Centre, Randwick, NSW 2031, Australia.|Australian Centre for Nanomedicine and ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, UNSW Australia, Sydney, NSW 2052, Australia and.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: McCarroll
authors.affiliation: Tumour Biology and Targeting Program, Children's Cancer Institute, UNSW Lowy Cancer Research Centre, Randwick, NSW 2031, Australia.|Australian Centre for Nanomedicine and ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, UNSW Australia, Sydney, NSW 2052, Australia and.
authors.forename: Maria
authors.initials: M
authors.lastname: Kavallaris
mesh_terms: D001343:Autophagy / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014404:Tubulin / Q000235:genetics* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C498585:TUBB3 protein, human; D014404:Tubulin; D051058:Oncogene Protein v-akt; D005947:Glucose