14-3-3ζ negatively regulates mitochondrial biogenesis in GBM residual cells

Glioblastoma (GBM) is the most lethal primary brain tumour with a median survival of only 15 months. We have previously demonstrated the generation of an in vitro therapy resistance model that captures the residual resistant (RR) disease cells of GBM post-radiation. We also reported the proteomic landscape of parent, residual, and relapse cells using iTRAQ based quantitative proteomics of glioma cells. The proteomics data revealed significant up-regulation (fold change >1.5) of 14-3-3 zeta, specifically in GBM RR cells. This was further confirmed by western blots in residual cells generated from GBM cell lines and patient sample-derived short-term primary culture. ShRNA-mediated knockdown of 14-3-3 zeta radio-sensitized GBM cells and further stimulated therapy-induced senescence (TIS) and multinucleated giant cells (MNGCs) phenotype in RR cells. Intriguingly, 14-3-3 zeta knock-down residual cells also showed a significantly higher number of mitochondria and increased mtDNA content. Indeed, in vitro GST pull-down mass spectrometry analysis of GST tagged 14-3-3 zeta from RR cells identified novel interacting partners of 14-3-3 zeta involved in cellular metabolism. Taken together, here we identified novel inter-acting partners of 14-3-3 zeta and proposed an unconventional function of 14-3-3 zeta as a negative regulator of TIS and mitochondrial biogenesis in residual resistant cells and loss of which also radio-sensitize GBM cells.

Automated summary

The study identified significant up-regulation of 14-3-3 zeta in residual resistant GBM cells, and knocking down this protein sensitized GBM cells to radiation therapy. Additionally, reduction of 14-3-3 zeta resulted in increased mitochondrial content in residual cells.