Interplay between P-Glycoprotein Expression and Resistance to Endoplasmic Reticulum Stressors

Abstract

Multidrug resistance (MDR) is a phenotype of cancer cells with reduced sensitivity to a wide range of unrelated drugs. P-glycoprotein (P-gp)—a drug efflux pump (ABCB1 member of the ABC transporter gene family)—is frequently observed to be a molecular cause of MDR. The drug-efflux activity of P-gp is considered as the underlying mechanism of drug resistance against P-gp substrates and results in failure of cancer chemotherapy. Several pathological impulses such as shortages of oxygen and glucose supply, alterations of calcium storage mechanisms and/or processes of protein N-glycosylation in the endoplasmic reticulum (ER) leads to ER stress (ERS), characterized by elevation of unfolded protein cell content and activation of the unfolded protein response (UPR). UPR is responsible for modification of protein folding pathways, removal of misfolded proteins by ER associated protein degradation (ERAD) and inhibition of proteosynthesis. However, sustained ERS may result in UPR-mediated cell death. Neoplastic cells could escape from the death pathway induced by ERS by switching UPR into pro survival mechanisms instead of apoptosis. Here, we aimed to present state of the art information about consequences of P-gp expression on mechanisms associated with ERS development and regulation of the ERAD system, particularly focused on advances in ERS-associated therapy of drug resistant malignancies.

IFI6 is an effective therapeutic target in esophageal squamous cell carcinoma via the modulation of oxidative stress

“…To explain the mechanism by which ATP deprivation leads to this substantial increase in NOX4 levels, we reasoned that this increase is likely to be correlated with induction of ER stress. Previous studies showed that ER stress can be induced by various means, including ATP deprivation [36]. Consistent with this observation, our aforementioned GSEA of TCGA data also revealed a state of energy deprivation as well ER stress induction ( Figure 8E, Figure 6A).…”

A stress-responsive enhancer induces dynamic drug resistance in acute myeloid leukemia

“…Previous reports of ABCB1 responses to cellular stress have been contradictory, demonstrating induction or repression, even after exposure to the same stressor (35). These conflicting results might be consistent with the pleiotropic function of ATF4, which is able to orchestrate adaptation and survival or apoptosis depending on cellular context and the severity of the insult.…”

P-Glycoprotein/ABCB1 Might Contribute to Morphine/Cisplatin-Induced Hepatotoxicity in Rats

“…Interestingly, these latter studies suggested that up-regulation of P-gp caused resistance against CP, not by effluxing the anticancer drug out of the tumor cells, but rather via decreasing its apoptotic effect through down-regulating caspase 3. Indeed, P-gp, through its antiapoptotic mechanisms, was reported to promote cellular resistance against compounds that were not P-gp substrates [32]. Alternatively, some studies suggested the other way around, that CP could induce up-regulation of P-gp through caspase 3 [33].…”