ABCB1 and ABCC1 Function during TGF-β-Induced Epithelial-Mesenchymal Transition: Relationship between Multidrug Resistance and Tumor Progression

Abstract

Multidrug resistance (MDR) and induction of metastasis are some of the puzzles encountered during cancer chemotherapy. The MDR phenotype is associated with overexpression of ABC transporters, involved in drug efflux. Metastasis originates from the epithelial-mesenchymal transition (EMT), in which cells acquire a migratory phenotype, invading new tissues. ABC transporters’ role during EMT is still elusive, though cells undergoing EMT exhibit enhanced ABCB1 expression. We demonstrated increased ABCB1 expression but no change in activity after TGF-β-induced EMT in A549 cells. Moreover, ABCB1 inhibition by verapamil increased snail and fibronectin expression, an event associated with upregulation of ABCB1, evidencing coincident cell signaling pathways leading to ABCB1 and EMT-related markers transcription, rather than a direct effect of transport. Additionally, for the first time, increased ABCC1 expression and activity was observed after EMT, and use of ABCC1 inhibitors partially inhibited EMT-marker snail, although increased ABCC1 function translated into collateral sensibility to daunorubicin. More investigations must be done to evaluate the real benefits that the gain of ABC transporters might have on the process of metastasis. Considering ABCC1 is involved in the stress response, affecting intracellular GSH content and drug detoxification, this transporter could be used as a therapeutic target in cancer cells undergoing EMT.

Molecular Modeling Studies to Probe the Binding Hypothesis of Novel Lead Compounds against Multidrug Resistance Protein ABCB1

“…Finally, the MD simulation was performed using the isothermalisobaric (NPT) ensemble for all selected ligand-protein complexes; atmospheric pressure was maintained at 1.0 bar and the temperature was set to 303 K. To study the dynamics and stability of docked complexes, trajectories were recorded with approximately 250 frames for 100 ns. The average change in displacement of atoms with respect to the reference frame was measured and, to gain insights into the structural conformation throughout the simulations, the root mean structure deviation (RMSD) was calculated using Equation (2).…”

“…Intrinsic or acquired resistance to chemotherapy, known as multidrug resistance (MDR), is an obstacle in the treatment of cancer [1][2][3]. Several MDR-causing factors have been elucidated; however, accelerated drug efflux mediated by the overexpression of the ATP-binding cassette (ABC) transporters is commonly recognized as clinically important [4][5][6].…”

Insights on the Role of Polyphenols in Combating Cancer Drug Resistance

“…P-gp is ubiquitous in tissues involved in the absorption, secretion, and transport of substrates across cellular plasma membranes, but its low expression makes it difficult to detect. MDR-ABC transporters are found in a wide variety of tissues [ 70 ]. The epithelial lining of the gut, endothelial cells, bone marrow progenitor xenocells, peripheral blood lymphocytes, and natural killer cells all contain ABCB1 in mammals, while adrenal cortex cells include ABCB2.…”

Zinc finger proteins and ATP‐binding cassette transporter‐dependent multidrug resistance

“…82 The other study did not show a significant change in ABCB1 expression of TGF-β-induced EMT in lung carcinoma epithelial cells, suggesting other effectors in interacting with EMT-related ABCB1 and ABCC1 overexpressions. 83 However, the specific effects of TGF-β on ABC transporter dysregulations vary across different ABC proteins and experimental conditions 84 and therefore warrant further investigation. There are still few studies that demonstrated the involvement of the Wnt/βcatenin signalling pathway in developing SNAIL-induced EMT.…”