The pathways controlling autophagy and apoptosis should be targeted as the strategies to improve treatment of glioblastoma. The proteins to be targeted are Beclin, p62 and EGFR.
Survival related or anti-apoptotic protein such as Bcl2 were found to be upregulated in glioblastomas whereas autophagy proteins like Beclin were found to be downregulated. The autohagy (Atg) proteins function at several discrete but continuous steps in autophagy which include induction or selection/packaging of cargo, vesicle nucleation, vesicle elongation, vesicle docking and fusion with lysosomes, and degradation of vesicular contents. There is significant evidence showing overlap between these two pathways. Hence, we choose to target these pathways and proteins associated with them.
Beclin: Beclin -1, the mammalian orthologueof the yeast Atg6/Vps30 gene, is an essential mediator of autophagy and also has a role as a tumor suppressor. Beclin-1 forms a multimeric complex with Atg14, Vps34/class 3 phosphatidylinositol 3--‐kinase (PI3k), and Vps15; the formation of this complex is necessary for the formation of the autophagosome and contributes to the regulation of autophagy. The human Beclin-1 gene is monoallelically deleted or is underexpressed in breast, ovarian, prostate, and gastric cancer, and most malignant brain tumors. Reduced expression ofautophagic marker LC3B-II and Beclin-1 in glioblastoma multiforme indicates a downregulated autophagic capacity that relates to the progression of astrocytic tumors.
p62: Recent studies have identified some level of specificity of the cargo for degradation through autophagic receptors containing the Atg8‐family Interacting motif: p62 (also Known as sequestosome‐1), Atg19, Atg32, NBR1 and Nix. Autophagy‐related protein 8 (Atg8) is essential for the formation of autophagosomes. Atg8 and its mammalian homologue, LC3 (microtubule associated protein 1 light chain 3; LC3 for short), are cleaved and lipidated in an ubiquitin‐like sequence of conjugation reactions. This lipidation causes it to associate to autophagosomes. LC3-binding adaptor protein, p62, for example, also contains an ubiquitin--‐association domain and thus functions as a receptor that brings ubiquitin-positive aggregates to autophagosomes. p62 is an autophagy selective substrate and it accumulates when autophagy activity is reduced. Indeed, the level of p62 is often used as an indicator...