Disruption of redox homeostasis is a crucial factor in the development of drug resistance, which is a major problem facing current cancer treatment. Compared with normal cells, tumor cells generally exhibit higher levels of reactive oxygen species (ROS), which can promote tumor progression and development. Upon drug treatment, some tumor cells can undergo a process of ‘Redox Resetting’ to acquire a new redox balance with higher levels of ROS accumulation and stronger antioxidant systems. Evidence has accumulated showing that the ‘Redox Resetting’ enables cancer cells to become resistant to anticancer drugs by multiple mechanisms, including increased rates of drug efflux, altered drug metabolism and drug targets, activated prosurvival pathways and inefficient induction of cell death. In this article, we provide insight into the role of ‘Redox Resetting’ on the emergence of drug resistance that may contribute to pharmacological modulation of resistance.
GBM (glioblastoma multiforme) is the most common and aggressive brain tumor with no curative options available. Therefore, it is imperative to develop novel potent therapeutic drugs for GBM treatment. Here, we show that regorafenib, an oral multi-kinase inhibitor, exhibits superior therapeutic efficacy over temozolomide, the first-line chemotherapeutic agent for GBM treatment both in vitro and in vivo. Mechanistically, regorafenib directly stabilizes PSAT1 (phosphoserine aminotransferase 1), a critical enzyme for serine synthesis, to trigger PRKAA-dependent autophagy initiation and inhibit RAB11A-mediated autophagosomelysosome fusion, resulting in lethal autophagy arrest in GBM cells. Maintenance of PSAT1 at a high level is essential for regorafenib-induced GBM suppression. Together, our data provide novel mechanistic insights of regorafenib-induced autophagy arrest and suggest a new paradigm for effective treatment of GBM.
G-protein-coupled receptor 48 (GPR48) is an orphan receptor belonging to the G-protein-coupled receptors family, which plays an important role in the development of various organs and cancer development and progression such as gastric cancer and colorectal cancer (CRC). However, the prognostic value of GPR48 expression in patients with CRC has not been reported. In this study, we observed that GPR48 was overexpressed in primary CRC and metastatic lymph nodes and closely correlated with tumor invasion and metastasis. Multivariate analysis indicated that high GPR48 expression was a poor prognostic factor for overall survival in CRC patients. In vitro and in vivo assays demonstrated that enforced expression of GPR48 contributed to enhance migration and invasion of cancer cells and tumor metastasis. In addition, we found that GPR48 increased nuclear β-catenin accumulation, T-cell factor 4 (TCF4) transcription activity, and expression of its target genes including Cyclin D1 and c-Myc in CRC cells. Correlation analysis showed that GPR48 expression in CRC tissues was positively associated with β-catenin expression. Upregulation of GPR48 resulted in increased phosphorylation of glycogen synthase kinase 3β, Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) in CRC cells, while inhibition of PI3K/Akt and mitogen-activated protein kinase /ERK1/2 pathways was sufficient to abolish the effect of GPR48 on β-catenin/TCF signaling. Taken together, GPR48 could serve as both a prognostic biomarker and a therapeutic target for resectable CRC patients.
Cancer cells maintain their intracellular ROS concentrations at required levels for their survival. Changes in ROS concentrations can regulate biochemical signaling mechanisms that control cell function. It has been demonstrated that ROS regulate the cellular events through redox regulation of redox-sensitive proteins (redox sensors). Upon oxidative stress, redox sensors undergo redox modifications that cause the allosteric changes of these proteins and endow them with different functions. Understanding the altered functions of redox sensors and the underlying mechanisms is critical for the development of novel cancer therapeutics. Recently, a series of high-throughput proteomics approaches have been developed for screening redox processes. In this manuscript, we review these methodologies and discuss the important redox sensors recently identified that are related to cancer.
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