Protein quality control allows eukaryotes to maintain proteostasis under the stress of constantly changing conditions. In this review, we discuss the current literature on PQC, highlighting flaws that must exist for malignancy to occur. At the nidus of PQC, the expression of BAG1-6 reflects the cell environment; each isoform directs proteins toward different, parallel branches of the quality control cascade. The sum of these branches creates a net shift toward either homeostasis or apoptosis. With an established role in ALP, Bag3 is necessary for cell survival in stress conditions including those of the cancerous niche (i.e., hypoxia, hypermutation). Evidence suggests that excessive Bag3-HSP70 activity not only sustains, but also propagates cancers. Its role is anti-apoptotic-which allows malignant cells to persist-and intercellular-with the production of infectious 'oncosomes' enabling cancer expansion and recurrence. While Bag3 has been identified as a key prognostic indicator in several cancer types, its investigation is limited regarding glioblastoma. The cochaperone HSP70 has been strongly linked with GBM, while ALP inhibitors have been shown to improve GBM susceptibility to chemotherapeutics. Given the highly resilient, frequently recurrent nature of GBM, the targeting of Bag3 is a necessary consideration for the successful and definitive treatment of GBM.
Keywords: apoptosis; autophagic–lysosomal pathway; autophagy; cancer; glioblastoma; protein quality control; proteostasis; treatment-resistant cancer; ubiquitin proteasome system.