Teaching an old dog new tricks: reactivated developmental signaling pathways regulate ABCB1 and chemoresistance in cancer

Abstract

Oncogenic multidrug resistance (MDR) is a multifactorial phenotype intimately linked to deregulated expression of detoxification transporters. Drug efflux transporters, particularly the MDR P-glycoprotein ABCB1, represent a central mechanism by which not only chemotherapeutic drugs are extruded or sequestered to prevent drug delivery to their intracellular targets, but also for inhibiting apoptotic cell death cues, such as removal of proapoptotic signals. Several cell populations exhibiting the MDR phenotype co-exist within a tumor, such as cells forming the bulk tumor cell mass, cancer stem cells, and cancer persister cells. The key to regulation of ABCB1 expression is the cellular transcriptional machinery. Developmental signaling pathways (e.g, Hedgehog, Notch, Wnt/β-catenin, TGFβ, PITX2) are pivotal in governing cell proliferation, survival, differentiation and guiding cell migration during embryogenesis, and their reactivation during carcinogenesis, which is of particular significance for tumor initiation, progression, and metastasis, also leads to the upregulation of ABCB1. These pathways also drive and maintain cancer cell stemness, for which ABCB1 is used as a marker. In this review, the contribution of canonical and non-canonical developmental signaling pathways in transcriptional regulation of ABCB1 to confer MDR in cancer is delineated.

Dysregulated Tear Film Proteins in Macular Edema Due to the Neovascular Age-Related Macular Degeneration Are Involved in the Regulation of Protein Clearance, Inflammation, and Neovascularization

“…One of the proteins crucial for the BRB development, ATP-dependent translocase ABCB1, was found to be upregulated in our study. ABCB1 is responsible for the cellular transport, being an efflux pump, and is commonly associated with various types of cancers, due to its role in the multidrug resistance (MDR) [ 39 , 40 , 41 ].…”

Carnosine Potentiates Doxorubicin-Induced Cytotoxicity in Resistant NCI/ADR-RES Cells by Inhibiting P-Glycoprotein—In Silico and In Vitro Evidence

“…Resistance of the cancer cell to chemotherapy exaggerates the problem of increased cancer-associated mortality and morbidity [ 1 ]. The increased expression and activity of P-gp diminishes drug delivery to cellular targets and increases the MDR of cancers [ 2 , 4 , 5 ]. Indeed, clinical evidence implicates P-gp with therapy failure and poor prognosis [ 7 , 8 ].…”

“…One important mechanism by which cancer cells resist cytotoxic drugs is increasing the expression of specific efflux pumps that shuttle organic molecules to the outside of the cell across the plasma membrane, preventing their intracellular accumulation to cytotoxic levels and ultimately leading to therapeutic failure [ 2 , 3 ]. These transmembrane efflux pumps include P-glycoprotein (P-gp), a member of the ATP-binding cassette (ABC) family of transporters that are associated with cancer drug resistance [ 4 , 5 ]. Thus, targeting these transporters would increase treatment efficacy and decrease cancer-associated mortality [ 3 ].…”

“…Contrarily, the expression and function of such transport systems largely determine the susceptibility of cancer cells to chemotherapeutic agents [ 2 , 3 ]. The increased expression and/or activity of P-gp, encoded in humans by the ABCB1 gene, confers resistance to anticancer drugs [ 4 , 5 ]. Clinically, tumors overexpressing P-gp are more resistant to chemotherapy and correlate with poor patient prognosis [ 7 , 8 ].…”

The Effect of Rifampicin on the Induction of MDR1/P-gp Activity in Proinflammatory Human Macrophages

“…Согласно имеющимся данным, область промотора гена MDR1 содержит множественные сайты связывания для различных факторов транскрипции, включая Myc, Sp1, AP-1, NF-kB и другие [20]. Одна из современных гипотез предполагает взаимодействие PXR (прегнановый Х рецептор) с областью промотора гена MDR1.…”