Rutaecarpine Increases Anticancer Drug Sensitivity in Drug-Resistant Cells through MARCH8-Dependent ABCB1 Degradation

Abstract

The overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) subfamily B member 1 (ABCB1; P-glycoprotein; MDR1) in some types of cancer cells is one of the mechanisms responsible for the development of multidrug resistance (MDR), which leads to the failure of chemotherapy. Therefore, it is important to inhibit the activity or reduce the expression level of ABCB1 to maintain an effective intracellular level of chemotherapeutic drugs. In this study, we found that rutaecarpine, a bioactive alkaloid isolated from Evodia Rutaecarpa, has the capacity to reverse ABCB1-mediated MDR. Our data indicated that the reversal effect of rutaecarpine was related to the attenuation of the protein level of ABCB1. Mechanistically, we demonstrated that ABCB1 is a newly discovered substrate of E3 ubiquitin ligase membrane-associated RING-CH 8 (MARCH8). MARCH8 can interact with ABCB1 and promote its ubiquitination and degradation. In short, rutaecarpine increased the degradation of ABCB1 protein by upregulating the protein level of MARCH8, thereby antagonizing ABCB1-mediated MDR. Notably, the treatment of rutaecarpine combined with other anticancer drugs exhibits a therapeutic effect on transplanted tumors. Therefore, our study provides a potential chemotherapeutic strategy of co-administrating rutaecarpine with other conventional chemotherapeutic agents to overcome MDR and improve therapeutic effect.

Rutaecarpine prevents the malignant biological properties of breast cancer cells by the miR-149-3p/S100A4 axis

“…T17110). The BC cells were treated with 0, 1, 5, 10, 20, and 40 µM RUT for 0, 12, 24, 48, and 72 h ( 25 , 26 ).…”

Progress in the studies on the molecular mechanisms associated with multidrug resistance in cancers

“…Series of specific intracellular conditions of MDR cancer cells, such as the newly balanced protein-degradation system, e . g ., the ubiquitination-degradation which ubiquitin ligase Cbl-b (at low level) or E3 ubiquitin ligase membrane-associated RING-CH 8 (MARCH8) participate in 164 , 165 , 166 , metabolism system 167 , cell membrane cholesterol homeostasis 168 , endoplasmic reticulum stress 169 , ion channels such as CLC chloride channels 170 , abnormal levels of intracellular glutathione (GSH) 171 , ATP 172 , metabolites such as methylglyoxal (MG) 167 , and so on, may develop the biophysical function adapted to drug press, and maintain the MDR activity in cancer cells. Although more intensive studied are required for elucidate the mechanisms behind, increasing attention has been attracted into this field and quite a few biomaterials have already been explored with potential to reverse MDR by targeting the factors influencing intracellular homeostasis 165 , 173 .…”

Protein degradation: expanding the toolbox to restrain cancer drug resistance

“…MARCH8, a member of the membrane-associated RING-CH (MARCH) protein family, is a transmembrane E3 ligase that targets glycoproteins for lysosomal destruction [ 58 ], whose downregulation modulates the drug sensitivity of breast cancer cells [ 59 ]. Mechanistically, MARCH8 can interact with ABCB1 and promote its ubiquitination and degradation, thereby antagonizing ABCB1-mediated drug efflux [ 60 ].…”