Pyroptosis, ferroptosis, and autophagy cross-talk in glioblastoma opens up new avenues for glioblastoma treatment

Abstract

Glioma is a common primary tumor of the central nervous system (CNS), with glioblastoma multiforme (GBM) being the most malignant, aggressive, and drug resistant. Most drugs are designed to induce cancer cell death, either directly or indirectly, but malignant tumor cells can always evade death and continue to proliferate, resulting in a poor prognosis for patients. This reflects our limited understanding of the complex regulatory network that cancer cells utilize to avoid death. In addition to classical apoptosis, pyroptosis, ferroptosis, and autophagy are recognized as key cell death modalities that play significant roles in tumor progression. Various inducers or inhibitors have been discovered to target the related molecules in these pathways, and some of them have already been translated into clinical treatment. In this review, we summarized recent advances in the molecular mechanisms of inducing or inhibiting pyroptosis, ferroptosis, or autophagy in GBM, which are important for treatment or drug tolerance. We also discussed their links with apoptosis to better understand the mutual regulatory network among different cell death processes. Video Abstract.

Keywords: Autophagy; Drug tolerance; Ferroptosis; Glioblastoma (GBM); Molecular mechanism; Pyroptosis; Temozolomide (TMZ).

Fig. 1

The molecular basis of pyroptosis and its regulation mode in GBM. A The miRNA-214 negatively regulates the mRNA of caspase-1. The Knockdown his-circ-0001836 activates caspase-1 and reduces the methylation of the NLRP1 promoter region. B The drugs: Galangin, Kaempferol, and Benimidazoles can induce pyroptosis in GBM by activating caspase-1

Fig. 2

The regulatory mechanism of ferroptosis in GBM

Fig. 3

The molecular basis of autophagy and its regulatory mode in GBM. Autophagy induced by drugs or stress in GBM can be divided into two types: cytotoxic autophagy and protective autophagy. Usually, the former exerts negative impact on the growth of GBM, while the latter is just the opposite, and as shown in (A) and (B), the two types of autophagy can be respectively induced and inhibited by drugs. In addition, as the (D) and (E) show, the occurrence cytotoxic autophagy and protective autophagy is related to a variety of factors, such as LMP induced by lysosomotropic agents, hypoxic TME, and nuclear or cytoplasmic localization of TP53, etc. Finally, (C) shows the whole process of autophagy, which can be blocked by CQ and HCQ