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.
Highlights
Bacterial resistance to antibiotic drugs was first described after the discovery that penicillin prompted bacteria to develop several important defense mechanisms, including the expression of efflux transporters in the outer cell wall
The broad range of substrates used by these transport proteins resulted in coining the term multidrug resistance (MDR) as pathogens can limit the accumulation of drugs targeted against them[1]
Development of the “fourth generation” ABCB1 modulators is focused on already available natural compounds[6], yet it is becoming increasingly apparent that MDR is a multifactorial phenomenon that will require targeting of a mechanism underlying several MDR-contributing factors[7,8]
Summary
Bacterial resistance to antibiotic drugs was first described after the discovery that penicillin prompted bacteria to develop several important defense mechanisms, including the expression of efflux transporters in the outer cell wall. In a study performed on breast cancer cells, binding of hyaluronan to the CSC marker, CD44+, a target gene of Wnt signaling[223], upregulated HAT CBP/p300, promoting acetylation of b-catenin and the inflammatory transcription factor, NF-κB-p65, leading to activation of TCF/LEF and NF-κB-specific transcription. This resulted in upregulation of ABCB1 and the anti-apoptotic gene, Bcl-xL (BCL2L1), and promoted chemoresistance in MCF-7 cells[224]. Wnt5a increases cAMP response elements and TCF/LEF transcriptional activity, ABCB1 and chemoresistance in MDR cancer cells, suggesting that PKA dependent non-canonical Wnt signaling regulates ABCB1 expression[233]. Rather than preventing transcription through blockade of the RNA polymerase, repressors can modify DNA looping by binding at multiple DNA sites, priming a transcription site to modulate cellular responsiveness or fine-tuning the transcriptional response[288]
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