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

• Published in: International journal of molecular sciences 2023-03, Vol.24 (7), p.6046
• Main Authors: da Costa, Kelli Monteiro, Freire-de-Lima, Leonardo, da Fonseca, Leonardo Marques, Previato, José Osvaldo, Mendonça-Previato, Lucia, Valente, Raphael do Carmo
• Format: Article
• Language: English
• Subjects: ABC transporters; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP-Binding Cassette Transporters - metabolism; Cancer; Cell adhesion & migration; Cell Line, Tumor; Cell signaling; Cellular signal transduction; Chemotherapy; Cytokines; Daunorubicin; Detoxification; Development and progression; Drug resistance in microorganisms; Drug Resistance, Multiple; Drug Resistance, Neoplasm - genetics; Efflux; Epithelial-Mesenchymal Transition; Extracellular matrix; Fibronectin; Genotype & phenotype; Glycoproteins; Growth factors; Humans; Lung cancer; Lung diseases; Medical prognosis; Melanoma; Metastases; Metastasis; MRP1; Multidrug resistance; Multidrug Resistance-Associated Proteins - metabolism; Multidrug resistant organisms; Neoplasms - drug therapy; Neoplasms - genetics; P-glycoprotein; Phenotypes; Stem cells; TGF-β; Therapeutic targets; Transcription factors; Transforming Growth Factor beta; Transforming growth factor-b; Transforming growth factors; Tumors; Verapamil
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24076046

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.