The cell cycle involves a network of proteins that modulate the sequence and timing of proliferation events. Unregulated proliferation is the most fundamental hallmark of cancer; thus, changes in cell cycle control are at the heart of malignant transformation processes. Several cellular processes can interfere with the cell cycle, including autophagy, the catabolic pathway involved in degradation of intracellular constituents in lysosomes. According to the mechanism used to deliver cargo to the lysosome, autophagy can be classified as macroautophagy (MA), microautophagy (MI), or chaperone-mediated autophagy (CMA). Distinct from other autophagy types, CMA substrates are selectively recognized by a cytosolic chaperone, one-by-one, and then addressed for degradation in lysosomes. The function of MA in cell cycle control, and its influence in cancer progression, are already well-established. However, regulation of the cell cycle by CMA, in the context of tumorigenesis, has not been fully addressed. This review aims to present and debate the molecular mechanisms by which CMA can interfere in the cell cycle, in the context of cancer. Thus, cell cycle modulators, such as MYC, hypoxia-inducible factor-1 subunit alpha (HIF-1α), and checkpoint kinase 1 (CHK1), regulated by CMA activity will be discussed. Finally, the review will focus on how CMA dysfunction may impact the cell cycle, and as consequence promote tumorigenesis.
Glioblastoma is a severe type of brain tumor with a poor prognosis and few therapy options. Temozolomide (TMZ) is one of these options, however, with limited success, and failure is mainly due to tumor resistance. In this work, genome-wide CRISPR-Cas9 lentiviral screen libraries for gene knockout or activation were transduced in the human glioblastoma cell line, aiming to identify genes that modulate TMZ resistance. The sgRNAs enriched in both libraries in surviving cells after TMZ treatment were identified by next-generation sequencing (NGS). Pathway analyses of gene candidates on knockout screening revealed several enriched pathways, including the mismatch repair and the Sonic Hedgehog pathways. Silencing three genes ranked on the top 10 list (MSH2, PTCH2, and CLCA2) confirm cell protection from TMZ-induced death. In addition, a CRISPR activation library revealed that NRF2 and Wnt pathways are involved in TMZ resistance. Consistently, overexpression of FZD6, CTNNB1, or NRF2 genes significantly increased cell survival upon TMZ treatment. Moreover, NRF2 and related genes detected in this screen presented a robust negative correlation with glioblastoma patient survival rates. Finally, several gene candidates from knockout or activation screening are targetable by inhibitors or small molecules, and some of them have already been used in the clinic.
Glioblastoma patients have a poor prognosis mainly due to temozolomide (TMZ) resistance. NRF2 is an important transcript factor involved in chemotherapy resistance due to its protective role in the transcription of genes involved in cellular detoxification and prevention of cell death processes, such as ferroptosis. However, the relation between NRF2 and iron-dependent cell death in glioma is still poorly understood. Therefore, in this study, we analyzed the role of NRF2 in ferroptosis modulation in glioblastoma cells. Two human glioblastoma cell lines (U251MG and T98G) were examined after treatment with TMZ, ferroptosis inducers (Erastin, RSL3), and ferroptosis inhibitor (Ferrostatin-1). Our results demonstrated that T98G was more resistant to chemotherapy compared to U251MG and showed elevated levels of NRF2 expression. Interestingly, T98G revealed higher sensitivity to ferroptosis, and significant GSH depletion upon system xc− blockage. NRF2 silencing in T98G cells (T98G-shNRF2) significantly reduced the viability upon TMZ treatment. On the other hand, T98G-shNRF2 was resistant to ferroptosis and reverted intracellular GSH levels, indicating that NRF2 plays a key role in ferroptosis induction through GSH modulation. Moreover, silencing of ABCC1, a well-known NRF2 target that diminishes GSH levels, has demonstrated a similar collateral sensitivity. T98G-siABCC1 cells were more sensitive to TMZ and resistant to Erastin. Furthermore, we found that NRF2 positively correlates with ABCC1 expression in tumor tissues of glioma patients, which can be associated with tumor aggressiveness, drug resistance, and poor overall survival. Altogether, our data indicate that high levels of NRF2 result in collateral sensitivity on glioblastoma via the expression of its pro-ferroptotic target ABCC1, which contributes to GSH depletion when the system xc− is blocked by Erastin. Thus, ferroptosis induction could be an important therapeutic strategy to reverse drug resistance in gliomas with high NRF2 and ABCC1 expression.
Glioblastoma multiforme is a lethal disease and represents the most common and severe type of glioma. Drug resistance and the evasion of cell death are the main characteristics of its malignancy, leading to a high percentage of disease recurrence and the patients’ low survival rate. Exploiting the modulation of cell death mechanisms could be an important strategy to prevent tumor development and reverse the high mortality and morbidity rates in glioblastoma patients. Ferroptosis is a recently described type of cell death, which is characterized by iron accumulation, high levels of polyunsaturated fatty acid (PUFA)-containing phospholipids, and deficiency in lipid peroxidation repair. Several studies have demonstrated that ferroptosis has a potential role in cancer treatment and could be a promising approach for glioblastoma patients. Thus, here, we present an overview of the mechanisms of the iron-dependent cell death and summarize the current findings of ferroptosis modulation on glioblastoma including its non-canonical pathway. Moreover, we focused on new ferroptosis-inducing compounds for glioma treatment, and we highlight the key ferroptosis-related genes to glioma prognosis, which could be further explored. Thereby, understanding how to trigger ferroptosis in glioblastoma may provide promising pharmacological targets and indicate new therapeutic approaches to increase the survival of glioblastoma patients.
The transcription factor NRF2 is constitutively active in glioblastoma, a highly aggressive brain tumor subtype with poor prognosis. Temozolomide (TMZ) is the primary chemotherapeutic agent for this type of tumor treatment, but resistance to this drug is often observed. This review highlights the research that is demonstrating how NRF2 hyperactivation creates an environment that favors the survival of malignant cells and protects against oxidative stress and TMZ. Mechanistically, NRF2 increases drug detoxification, autophagy, DNA repair, and decreases drug accumulation and apoptotic signaling. Our review also presents potential strategies for targeting NRF2 as an adjuvant therapy to overcome TMZ chemoresistance in glioblastoma. Specific molecular pathways, including MAPKs, GSK3β, βTRCP, PI3K, AKT, and GBP, that modulate NRF2 expression leading to TMZ resistance are discussed, along with the importance of identifying NRF2 modulators to reverse TMZ resistance and develop new therapeutic targets. Despite the significant progress in understanding the role of NRF2 in GBM, there are still unanswered questions regarding its regulation and downstream effects. Future research should focus on elucidating the precise mechanisms by which NRF2 mediates resistance to TMZ, and identifying potential novel targets for therapeutic intervention.
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