ßIII-Tubulin supports cell growth and proliferation of glucose-starved Non-small Cell Lung Cancer cells by modulating multiple stress response signalling pathways. — ASN Events
  1. Schedule
  2. Afternoon Tea/Poster Session
  3. ßIII-Tubulin supports cell growth and proliferation of glucose-starved Non-small Cell Lung Cancer cells by modulating multiple stress response signalling pathways.

ßIII-Tubulin supports cell growth and proliferation of glucose-starved Non-small Cell Lung Cancer cells by modulating multiple stress response signalling pathways. (#139)

Amelia Parker 1 , Joshua McCarroll 1 2 , Maria Kavallaris 1 2
  1. Children's Cancer Institute, Randwick, NSW, Australia
  2. ARC Centre for Convergent Bio-Nano Science and Technology, Australian Centre for Nanomedicine, UNSW, NSW, Australia

Aberrant expression of βIII-tubulin is associated with chemotherapy resistance and tumour aggressiveness in many epithelial cancers, including Non-small Cell Lung Cancer (NSCLC)1.  The ability of tumour cells to respond to stress induced by either chemotherapy treatment or the harsh tumour microenvironment is critical in determining patient outcome, which remains dismal for this disease.  With emerging evidence supporting a role for βIII-tubulin as a cellular survival factor in NSCLC2,3, this study aimed to investigate the role of βIII-tubulin in stress signalling in response to glucose starvation.

METHODS: βIII-tubulin shRNA or non-targeting control shRNA expressing NCI-H460 and A549 NSCLC cells were cultured in glucose-free media. Trypan Blue, BrdU and Annexin-V Apoptosis assays were used for proliferation and survival. Akt signalling, ER stress response and autophagic activity were monitored by western blotting. XBP-1 splicing assays and immunofluorescence detected ER stress induction and autophagy, respectively.

RESULTS: Suppression of βIII-tubulin expression reduced cell proliferation and viability in response to glucose starvation. Under basal and glucose starved conditions, Akt phosphorylation was dramatically reduced in cells with suppressed βIII-tubulin expression compared with control cells. Suppression of βIII-tubulin levels also induced the ER stress response to a greater extent in glucose starvation, as measured by levels of ER stress response proteins GRP78, ATF4 and CHOP and XBP-1 splicing assays. Suppression of βIII-tubulin also altered autophagic flux in both basal and glucose starved conditions. Furthermore, GRP78 co-immunoprecipitated with βIII-tubulin under glucose starved conditions.  These results indicate that βIII-tubulin modulates multiple stress response signalling pathways and promotes cell survival and proliferation in glucose starvation in NSCLC.

CONCLUSION: The influence of βIII-tubulin on multiple stress responses in glucose starved NSCLC provides mechanistic insight into how aberrant βIII-tubulin expression influences poor prognosis in NSCLC.

  1. Kavallaris, Nature Rev Cancer, 10:194-204, 2010.
  2. McCarroll et al., Cancer Res 70 :4995-5003, 2010.
  3. McCarroll et al., Cancer Res 75 :415-425, 2015.