Bortezomib abrogates temozolomide-induced autophagic flux through an ATG5 dependent pathway
Mohummad Aminur Rahman,
Maria L. Lotsberg,
Posted 23 Dec 2020
bioRxiv DOI: 10.1101/2020.12.20.423718
Posted 23 Dec 2020
Glioblastoma (GBM) is invariably resistant to temozolomide (TMZ) chemotherapy. Inhibiting the proteasomal pathway is an emerging strategy to accumulate damaged proteins and inhibit their lysosomal degradation. We hypothesized that bortezomib (BTZ) might sensitize GBM cells to TMZ. We examined change in autophagic flux after drug treatments and in combination with pharmacological inhibitors or CRISPR cas9 knockout of autophagy-related genes -5 and -7 (ATG5 and ATG7, respectively). Autophagic flux was increased in temozolomide resistant GBM cells as indicated by diminished levels of the autophagy markers LC3A/B-II and p62(SQSTM1), increased localisation of LC3A/B-II with STX17, higher long-lived protein degradation and no induction of apoptosis. In contrast, BTZ treatment abrogated autophagic flux by accumulation of LC3A/B-II and p62(SQSTM1) positive autophagosomes that did not fuse with lysosomes and reduced degradation of long-lived proteins. BTZ synergistically enhanced TMZ efficacy by attenuating cell proliferation, increased DNA damage and apoptosis. CRISPR Cas ATG5 knockout reversed BTZ-induced autophagy blockade and rescued the GBM treated cells from death. We conclude that bortezomib abrogates temozolomide induced autophagy through ATG5 dependent pathway.
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