Insulin resistance contributes to multidrug resistance in HepG2 cells via activation of the PERK signaling pathway and upregulation of Bcl-2 and P-gp

Li, Linjing; Li, Jing; Cheng, Yan; Chen, Jing; Shen, Minghui; Zhang, Shangdi; Wei, Hulai

doi:10.3892/or.2016.4632

Cited by 17 publications

(35 citation statements)

References 38 publications

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“…The knockout of Bak and Bax in β‐cells does not involve metabolic changes, indicating a role for BCL2 in metabolism besides its anti‐apoptotic function . In keeping with these results, induced insulin resistance in HepG2 cells upregulates BCL2 . How Bcl2 suppression leads to improved response to glucose has not been elucidated.…”

Section: Contacts Between Mitochondria and Other Organellesmentioning

confidence: 95%

Metabolic implications of organelle–mitochondria communication

2019

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Cellular organelles are not static but show dynamism—a property that is likely relevant for their function. In addition, they interact with other organelles in a highly dynamic manner. In this review, we analyze the proteins involved in the interaction between mitochondria and other cellular organelles, especially the endoplasmic reticulum, lipid droplets, and lysosomes. Recent results indicate that, on one hand, metabolic alterations perturb the interaction between mitochondria and other organelles, and, on the other hand, that deficiency in proteins involved in the tethering between mitochondria and the ER or in specific functions of the interaction leads to metabolic alterations in a variety of tissues. The interaction between organelles is an emerging field that will permit to identify key proteins, to delineate novel modulation pathways, and to elucidate their implications in human disease.

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Section: Contacts Between Mitochondria and Other Organellesmentioning

confidence: 95%

Metabolic implications of organelle–mitochondria communication

2019

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“…Recent evidence suggests that ERS is involved in the regulation of resistance to chemotherapy either independent or dependent on P-gp [ 137 , 138 , 139 , 140 , 141 ]. Cagnetta et al reported that P-gp inhibitors induced ERS and ERS blockage strongly reduced the cytotoxic effect of the treatment in leukemic cells [ 137 ].…”

Section: Er Stress Cancer and Mdrmentioning

confidence: 99%

“…The mechanism underlying the induction of ERS by P-gp inhibition is not completely clear. However, the fact that insulin resistance promotes PERK mediated ERS, expression of Bcl-2 and P-gp in human hepatocarcinoma cells [ 138 ] indicated on strong relations between these ESR and P-gp function. In addition, expression of PERK in ERS resistant cells was increased and resulted in Nrf2 dependent transcription of the MRP1 gene.…”

Section: Er Stress Cancer and Mdrmentioning

confidence: 99%

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

et al. 2018

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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.

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“…(Bottom panel), EPI-MEND could not effectively avoid the over expression of P-gp, while siBCL-MEND and EPI/siBCL-2-MEND can significantly downregulate the expression of P-gp. It may be that there is a certain link between BCL-2 and P-gp [19], making the expression of P-gp decreased with the down-regulation of BCL-2. This result suggested that EPI/siBCL-2-MEND can be used to inhibit the multi-drug resistance of tumor cells.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…SiBCL-2 is usually used to inhibit the expression of BCL-2 gene to promote the apoptosis of tumor cells [17,18]. Studies have shown that PEKR pathway can regulate the expression of BCL-2 and P-gp in insulin resistant HepG 2 cells [19], which can be inferred that there is a link between the expression of BCL-2 and P-gp. We assumed that the expression of P-gp can be decreased by down-regulating the expression of BCL-2.…”

Section: Introductionmentioning

confidence: 99%

Lipid nanoparticle-based co-delivery of epirubicin and BCL-2 siRNA for enhanced intracellular drug release and reversing multidrug resistance

Han

Kou

et al. 2017

Artificial Cells, Nanomedicine, and Biotechnology

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At present, combined therapy has become an effective strategy for the treatment of cancer. Co-delivery of the chemotherapeutic drugs and siRNA can more effectively inhibit tumor growth by nano drug delivery systems (NDDSs). Here, we prepared and evaluated a multifunctional envelope-type nano device (MEND). This MEND was a kind of composite lipid-nanoparticles possessing both the properties of liposomes and nanoparticles. In this study, an acid-cleavable ketal containing poly (β-amino ester) (KPAE) was used to bind siBCL-2 and the KPAE/siBCL-2 complexes were further coated by epirubicin (EPI) containing lipid to form EPI/siBCL-2 dual loaded lipid-nanoparticles. The results showed that the average size of EPI/siBCL-2-MEND was about 120 nm, and the average zeta potential was about 41 mV. The encapsulation efficiency (EE) of EPI and siBCL-2 was 86.13% and 97.07%, respectively. EPI/siBCL-2 dual loaded lipid-nanoparticles showed enhanced inhibition efficiency than individual EPI-loaded liposomes on HepG cells by MTT assay. Moreover, western blot experiment indicated co-delivery of EPI/siBCL-2 can significantly down-regulate the expression of P-glycoprotein (P-gp), while free EPI and EPI-loaded liposomes up-regulated it. Therefore, the strategy of co-delivering EPI and siBCL-2 simultaneously by lipid-nanoparticles showed promising potential in reversing multidrug resistance of tumor cells.

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Insulin resistance contributes to multidrug resistance in HepG2 cells via activation of the PERK signaling pathway and upregulation of Bcl-2 and P-gp

Cited by 17 publications

References 38 publications

Metabolic implications of organelle–mitochondria communication

Metabolic implications of organelle–mitochondria communication

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

Lipid nanoparticle-based co-delivery of epirubicin and BCL-2 siRNA for enhanced intracellular drug release and reversing multidrug resistance

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