Autophagy Modulation and Its Implications on Glioblastoma Treatment

Abstract

Autophagy is a vital cellular process that functions to degrade and recycle damaged organelles into basic metabolites. This allows a cell to adapt to a diverse range of challenging conditions. Autophagy assists in maintaining homeostasis, and it is tightly regulated by the cell. The disruption of autophagy has been associated with many diseases, such as neurodegenerative disorders and cancer. This review will center its discussion on providing an in-depth analysis of the current molecular understanding of autophagy and its relevance to brain tumors. We will delve into the current literature regarding the role of autophagy in glioma pathogenesis by exploring the major pathways of JAK2/STAT3 and PI3K/AKT/mTOR and summarizing the current therapeutic interventions and strategies for glioma treatment. These treatments will be evaluated on their potential for autophagy induction and the challenges associated with their utilization. By understanding the mechanism of autophagy, clinical applications for future therapeutics in treating gliomas can be better targeted.

Keywords: JAK2/STAT3 signaling pathway; PI3K/AKT/mTOR signaling pathway; autophagy; glioblastoma; treatment.

Figure 1

Activating autophagy by targeting the JAK/STAT pathway. The JAK/STAT pathway is activated when cytokines bind to cell membrane JAK receptors. The drugs discussed in this review are listed within the figure and include pimozide, temozolomide (TMZ), momelotinib (MTB), pacritinib, and curcumin. Pimozide, TMZ, and MTB function to inhibit STAT3, which leads to the downstream effect of autophagy induction. Curcumin inhibits both JAK-1 and JAK-2, which ultimately leads to autophagy induction. Pacritinib specifically inhibits JAK-2 and leads to autophagy induction as well.

Figure 2

Induction of autophagy by inhibiting the PI3K/AKT/mTOR pathway. The PI3K/AKT/mTOR pathway is activated when growth factors activate Receptor Tyrosine Kinase (RTK), which then leads to activation of PI3K. The drugs affecting the PI3K/AKT/mTOR pathway are listed within the figure and include rapamycin, curcumin, ganoderic acid DM (GA-DM), ivermectin, ABTL0812, metformin, SW33, and temozolomide (TMZ). Rapamycin, TMZ, metformin, and SW33 inhibit mTORC1, which leads to autophagy induction. Curcumin inhibits mTORC2, which promotes induction of autophagy. GA-DM activates AMPK, which leads to activation of TSC1/TSC2 and, ultimately, autophagy induction. Ivermectin and ABTL0812 inhibit AKT, which leads to autophagy induction as well.