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Cryptotanshinone Inhibits ERα-Dependent and -Independent BCRP Oligomer Formation to Reverse Multidrug Resistance in Breast Cancer.

ABSTRACT: Both long-term anti-estrogen therapy and estrogen receptor-negative breast cancer contribute to drug resistance, causing poor prognosis in breast cancer patients. Breast cancer resistance protein (BCRP) plays an important role in multidrug resistance. Here, we show that cryptotanshinone (CPT), an anti-estrogen compound, inhibited the oligomer formation of BCRP on the cell membrane, thus blocking its efflux function. The inhibitory effect of CPT on BCRP was dependent on the expression level of estrogen receptor α (ERα) in ERα-positive breast cancer cells. Furthermore, ERα-negative breast cancer cells with high expression of BCRP were also sensitive to CPT because CPT was able to bind to BCRP and inhibit its oligomer formation on the cell membrane, suggesting that the high level of BCRP expression is crucial for CPT to reverse drug resistance. The combination of CPT and chemotherapeutic agents displayed enhanced anticancer effects. The results suggest that CPT is a novel BCRP inhibitor via blocking the oligomer formation of BCRP on the cell membrane. CPT is able to inhibit the activity of BCRP in an ERα-dependent and -independent manner, sensitizing breast cancer cells to chemotherapy.

SUBMITTER: Ni W

PROVIDER: S-EPMC8100513 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2) is an ATP-binding cassette (ABC) transporter identified as a molecular cause of multidrug resistance (MDR) in diverse cancer cells. BCRP physiologically functions as a part of a self-defense mechanism for the organism; it enhances elimination of toxic xenobiotic substances and harmful agents in the gut and biliary tract, as well as through the blood-brain, placental, and possibly blood-testis barriers. BCRP recognizes and transports numerous anticancer drugs including conventional chemotherapeutic and targeted small therapeutic molecules relatively new in clinical use. Thus, BCRP expression in cancer cells directly causes MDR by active efflux of anticancer drugs. Because BCRP is also known to be a stem cell marker, its expression in cancer cells could be a manifestation of metabolic and signaling pathways that confer multiple mechanisms of drug resistance, self-renewal (stemness), and invasiveness (aggressiveness), and thereby impart a poor prognosis. Therefore, blocking BCRP-mediated active efflux may provide a therapeutic benefit for cancers. Delineating the precise molecular mechanisms for BCRP gene expression may lead to identification of a novel molecular target to modulate BCRP-mediated MDR. Current evidence suggests that BCRP gene transcription is regulated by a number of trans-acting elements including hypoxia inducible factor 1α, estrogen receptor, and peroxisome proliferator-activated receptor. Furthermore, alternative promoter usage, demethylation of the BCRP promoter, and histone modification are likely associated with drug-induced BCRP overexpression in cancer cells. Finally, PI3K/AKT signaling may play a critical role in modulating BCRP function under a variety of conditions. These biological events seem involved in a complicated manner. Untangling the events would be an essential first step to developing a method to modulate BCRP function to aid patients with cancer. This review will present a synopsis of the impact of BCRP-mediated MDR in cancer cells, and the molecular mechanisms of acquired MDR currently postulated in a variety of human cancers.

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Cryptotanshinone Inhibits ERα-Dependent and -Independent BCRP Oligomer Formation to Reverse Multidrug Resistance in Breast Cancer.

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