What sustains the multidrug resistance phenotype beyond ABC efflux transporters? Looking beyond the tip of the iceberg
2019
Аутори:
Alexa-Stratulat, TeodoraPešić, Milica
Čipak Gašparović, Ana
Trougakos, Ioannis
Riganti, Chiara
Тип документа:
Чланак у часопису (Објављена верзија)
,
© 2019 Elsevier Ltd
Метаподаци
Приказ свих података о документуАпстракт:
Identification of multidrug (MDR) efflux transporters that belong to the ATP-Binding Cassette (ABC) superfamily, represented an important breakthrough for understanding cancer multidrug resistance (MDR) and its possible overcoming. However, recent data indicate that drug resistant cells have a complex intracellular physiology that involves constant changes in energetic and oxidative-reductive metabolic pathways, as well as in the molecular circuitries connecting mitochondria, endoplasmic reticulum (ER) and lysosomes. The aim of this review is to discuss the key molecular mechanisms of cellular reprogramming that induce and maintain MDR, beyond the presence of MDR efflux transporters. We specifically highlight how cancer cells characterized by high metabolic plasticity – i.e. cells able to shift the energy metabolism between glycolysis and oxidative phosphorylation, to survive both the normoxic and hypoxic conditions, to modify the cytosolic and mitochondrial oxidative-reductive metabolism, are more prone to adapt to exogenous stressors such as anti-cancer drugs and acquire a MDR phenotype. Similarly, we discuss how changes in mitochondria dynamics and mitophagy rates, changes in proteome stability ensuring non-oncogenic proteostatic mechanisms, changes in ubiquitin/proteasome- and autophagy/lysosome-related pathways, promote the cellular survival under stress conditions, along with the acquisition or maintenance of MDR.
After dissecting the complex intracellular crosstalk that takes place during the development of MDR, we suggest that mapping the specific adaptation pathways underlying cell survival in response to stress and targeting these pathways with potent pharmacologic agents may be a new approach to enhance therapeutic efficacy against MDR tumors.
Кључне речи:
ATP-binding cassette transporters; Oxidative-reductive metabolism; Mitochondria; Endoplasmic reticulum; Proteasome; Autophagy; LysosomesИзвор:
Drug Resistance Updates, 2019, 46, 100643-Финансирање / пројекти:
- Italian Association of Cancer Research (IG21408)
- TASCMAR (EU-H2020/634674)
- BIOIMAGING-GR (MIS 5002755)
- PlantUP-GR (MIS 5002803)
- Идентификација молекуларних маркера за предикцију прогресије тумора, одговора на терапију и исхода болести (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
- COST Action 17104 STRATAGEM
DOI: 10.1016/j.drup.2019.100643
ISSN: 1368-7646
PubMed: 31493711