Importance of Autophagy Regulation in Glioblastoma with Temozolomide Resistance

Abstract

Glioblastoma (GBM) is the most aggressive and common malignant and CNS tumor, accounting for 47.7% of total cases. Glioblastoma has an incidence rate of 3.21 cases per 100,000 people. The regulation of autophagy, a conserved cellular process involved in the degradation and recycling of cellular components, has been found to play an important role in GBM pathogenesis and response to therapy. Autophagy plays a dual role in promoting tumor survival and apoptosis, and here we discuss the complex interplay between autophagy and GBM. We summarize the mechanisms underlying autophagy dysregulation in GBM, including PI3K/AKT/mTOR signaling, which is most active in brain tumors, and EGFR and mutant EGFRvIII. We also review potential therapeutic strategies that target autophagy for the treatment of GBM, such as autophagy inhibitors used in combination with the standard of care, TMZ. We discuss our current understanding of how autophagy is involved in TMZ resistance and its role in glioblastoma development and survival.

Keywords: autophagy; chemoresistance; glioblastoma; temozolomide.

Figure 1

Receptor tyrosine kinases (RTKs), epidermal growth factor receptor (EGFR), and its variant EGFRvIII activate the PI3K/AKT signaling pathway, subsequently influencing mTOR activity. Activation of RTKs, EGFR, and EGFRvIII leads to the phosphorylation and activation of PI3K, which converts PIP2 to PIP3 [18]. This conversion recruits and activates AKT, which in turn phosphorylates and activates mTOR. Activated mTOR functions as a major inhibitor of autophagy by phosphorylating and inhibiting key autophagy-initiating proteins, such as ULK1/2 [52]. This inhibition prevents the formation of autophagosomes and, subsequently, blocks the autophagic process, allowing for the accumulation of damaged proteins and organelles within the cell. mTOR pathway: Inhibition of autophagy occurs through the mTOR pathway, which is activated by abundant nutrients. Under conditions of nutrient deficiency, energy deficiency, and oxidative stress, mTOR is inhibited, leading to the induction of autophagy.

Figure 2

Beclin-1 forms a complex with PI3K-III, ATG9, and ATG14 to initiate autophagosome formation. LC3-I is converted to LC3-II by ATG7 and ATG13 [53]. LC3-II binds to the autophagosome membrane and helps it expand. The ATG12-ATG5-ATG16L1 complex is essential for the extension and formation of the autophagosome membrane and promotes growth [53]. Mature autophagosomes fuse with lysosomes to form autolysosomes. Lysosomal digestive enzymes are transported into the autophagosome. Lysosome and autophagosome fuse to break down damaged organelles and dysfunctional substances to create new proteins and various substances.

Figure 3

Temozolomide (TMZ) treatment leads to an increase in reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress in cancer cells [86] (A,B). These stress factors induce autophagy as a survival mechanism in cancer cells. Bevacizumab treatment causes an increase in hypoxia within the tumor microenvironment. Hypoxia acts as a trigger for autophagy, further promoting the survival of cancer cells under stress conditions. Radiation therapy results in an increase in ROS levels. The heightened ROS levels stimulate autophagy, enabling cancer cells to cope with the oxidative damage induced by radiation. Post-TMZ surgery, following TMZ treatment and surgical intervention, residual glioma stem cells (GSCs) survive. These GSCs, now under selective pressure, form resistant cell populations, leading to the development of drug resistance. This figure illustrates the complex interplay between various treatments (TMZ, bevacizumab, radiation) and their impact on the induction of autophagy in cancer cells. It highlights the role of autophagy in promoting cancer cell survival and the subsequent emergence of drug-resistant cells.