SMAR1 repression by pluripotency factors and consequent chemoresistance in breast cancer stem-like cells is reversed by aspirin

The high abundance of drug efflux pumps in cancer stem cells (CSCs) contributes to chemotherapy resistance. The transcriptional regulator SMAR1 suppresses CSC expansion in colorectal cancer, and increased abundance of SMAR1 is associated with better prognosis. Here, we found in breast tumors that the expression of SMAR1 was decreased in CSCs through the cooperative interaction of the pluripotency factors Oct4 and Sox2 with the histone deacetylase HDAC1. Overexpressing SMAR1 sensitized CSCs to chemotherapy through SMAR1-dependent recruitment of HDAC2 to the promoter of the gene encoding the drug efflux pump ABCG2. Treating cultured CSCs or 4T1 tumor-bearing mice with the nonsteroidal anti-inflammatory drug aspirin restored SMAR1 expression and ABCG2 repression and enhanced tumor sensitivity to doxorubicin. Our findings reveal transcriptional mechanisms regulating SMAR1 that also regulate cancer stemness and chemoresistance and suggest that, by restoring SMAR1 expression, aspirin might enhance chemotherapeutic efficacy in patients with stem-like tumors.

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Deep mutational scan of a drug efflux pump reveals its structure-function landscape

10.1101/2021.10.01.462730 ◽

2021 ◽

Author(s):

Gianmarco Meier ◽

Sujani Thavarasah ◽

Kai Ehrenbolger ◽

Cedric A.J. Hutter ◽

Lea M. Hürlimann ◽

...

Keyword(s):

Efflux Pump ◽

Resistance Mechanism ◽

Binding Pocket ◽

Drug Efflux ◽

Activity Profile ◽

Substrate Binding Pocket ◽

High Affinity Binding Site ◽

Drug Efflux Pumps ◽

Drug Efflux Pump ◽

Positively Charged

Drug efflux is a common resistance mechanism found in bacteria and cancer cells. Although several structures of drug efflux pumps are available, they provide only limited functional information on the phenomenon of drug efflux. Here, we performed deep mutational scanning (DMS) on the bacterial ATP binding cassette (ABC) transporter EfrCD to determine the drug efflux activity profile of more than 1500 single variants. These systematic measurements revealed that the introduction of negative charges at different locations within the large substrate binding pocket results in strongly increased efflux activity towards positively charged ethidium, while additional aromatic residues did not display the same effect. Data analysis in the context of an inward-facing cryo-EM structure of EfrCD uncovered a high affinity binding site, which releases bound drugs through a peristaltic transport mechanism as the transporter transits to its outward-facing conformation. Finally, we identified substitutions resulting in rapid Hoechst influx without affecting the efflux activity for ethidium and daunorubicin. Hence, single mutations can convert the ABC exporter EfrCD into a drug-specific ABC importer.

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RamA Is an Alternate Activator of the Multidrug Resistance Cascade in Enterobacter aerogenes

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.7.2518-2523.2004 ◽

2004 ◽

Vol 48 (7) ◽

pp. 2518-2523 ◽

Cited By ~ 69

Author(s):

Renaud Chollet ◽

Jacqueline Chevalier ◽

Claude Bollet ◽

Jean-Marie Pages ◽

Anne Davin-Regli

Keyword(s):

Escherichia Coli ◽

Multidrug Resistance ◽

Type Strain ◽

Efflux Pump ◽

Regulatory Protein ◽

Enterobacter Aerogenes ◽

Transcriptional Activator ◽

Drug Efflux ◽

Gene Encoding ◽

Drug Efflux Pump

ABSTRACT Multidrug resistance (MDR) in Enterobacter aerogenes can be mediated by induction of MarA, which is triggered by certain antibiotics and phenolic compounds. In this study, we identified the gene encoding RamA, a 113-amino-acid regulatory protein belonging to the AraC-XylS transcriptional activator family, in the Enterobacter aerogenes ATCC 13048 type strain and in a clinical multiresistant isolate. Overexpression of RamA induced an MDR phenotype in drug-susceptible Escherichia coli JM109 and E. aerogenes ATCC 13048, as demonstrated by 2- to 16-fold-increased resistance to β-lactams, tetracycline, chloramphenicol, and quinolones, a decrease in porin production, and increased production of AcrA, a component of the AcrAB-TolC drug efflux pump. We show that RamA enhances the transcription of the marRAB operon but is also able to induce an MDR phenotype in a mar-deleted strain. We demonstrate here that RamA is a transcriptional activator of the Mar regulon and is also a self-governing activator of the MDR cascade.

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Membrane homoeostasis and multidrug resistance in yeast

Bioscience Reports ◽

10.1042/bsr20080071 ◽

2008 ◽

Vol 28 (4) ◽

pp. 217-228 ◽

Cited By ~ 17

Author(s):

Sneh Lata Panwar ◽

Ritu Pasrija ◽

Rajendra Prasad

Keyword(s):

Multidrug Resistance ◽

Efflux Pump ◽

Efflux Pumps ◽

Membrane Lipid ◽

Major Facilitator Superfamily ◽

Drug Efflux ◽

Proper Functioning ◽

Drug Efflux Pumps ◽

Drug Efflux Pump ◽

Major Facilitator

The development of MDR (multidrug resistance) in yeast is due to a number of mechanisms. The most documented mechanism is enhanced extrusion of drugs mediated by efflux pump proteins belonging to either the ABC (ATP-binding cassette) superfamily or MFS (major facilitator superfamily). These drug-efflux pump proteins are localized on the plasma membrane, and the milieu therein affects their proper functioning. Several recent studies demonstrate that fluctuations in membrane lipid composition affect the localization and proper functioning of the MDR efflux pump proteins. Interestingly, the efflux pumps of the ABC superfamily are particularly susceptible to imbalances in membrane-raft lipid constituents. This review focuses on the importance of the membrane environment in functioning of the drug-efflux pumps and explores a correlation between MDR and membrane lipid homoeostasis.

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P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells

Life Sciences ◽

10.1016/0024-3205(92)90537-y ◽

1992 ◽

Vol 51 (18) ◽

pp. 1427-1437 ◽

Cited By ~ 197

Author(s):

Akira Tsuji ◽

Tetsuya Terasaki ◽

Yasushi Takabatake ◽

Yoshiyuki Tenda ◽

Ikumi Tamai ◽

...

Keyword(s):

Endothelial Cells ◽

Efflux Pump ◽

Bovine Brain ◽

Drug Efflux ◽

Brain Capillary ◽

Brain Capillary Endothelial Cells ◽

P Glycoprotein ◽

Capillary Endothelial Cells ◽

Drug Efflux Pump

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Structure-property correlation in gallic acid and 4-cyanopyridine cocrystal and binding studies with drug efflux pump in bacteria

Journal of Molecular Structure ◽

10.1016/j.molstruc.2020.129279 ◽

2021 ◽

Vol 1225 ◽

pp. 129279

Author(s):

Shyam Goswami ◽

Arabinda Ghosh ◽

Karmajyoti Borah ◽

Anupam Mahanta ◽

Ankur K Guha ◽

...

Keyword(s):

Gallic Acid ◽

Efflux Pump ◽

Drug Efflux ◽

Structure Property ◽

Binding Studies ◽

Property Correlation ◽

Drug Efflux Pump

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Phytochemicals increase the antibacterial activity of antibiotics by acting on a drug efflux pump

MicrobiologyOpen ◽

10.1002/mbo3.212 ◽

2014 ◽

Vol 3 (6) ◽

pp. 885-896 ◽

Cited By ~ 34

Author(s):

Thelma Ohene‐Agyei ◽

Rumana Mowla ◽

Taufiq Rahman ◽

Henrietta Venter

Keyword(s):

Antibacterial Activity ◽

Efflux Pump ◽

Drug Efflux ◽

Drug Efflux Pump

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A Broad-Specificity Multidrug Efflux Pump Requiring a Pair of Homologous SMR-Type Proteins

Journal of Bacteriology ◽

10.1128/jb.182.8.2311-2313.2000 ◽

2000 ◽

Vol 182 (8) ◽

pp. 2311-2313 ◽

Cited By ~ 63

Author(s):

Donald L. Jack ◽

Michael L. Storms ◽

Jason H. Tchieu ◽

Ian T. Paulsen ◽

Milton H. Saier

Keyword(s):

Escherichia Coli ◽

Efflux Pump ◽

Multidrug Resistant ◽

Drug Efflux ◽

Multidrug Efflux ◽

Multidrug Efflux Pump ◽

Resistant Phenotype ◽

Small Multidrug Resistance ◽

Drug Efflux Pumps ◽

Broad Specificity

ABSTRACT The Bacillus subtilis genome encodes seven homologues of the small multidrug resistance (SMR) family of drug efflux pumps. Six of these homologues are paired in three distinct operons, and coexpression in Escherichia coli of one such operon,ykkCD, but not expression of either ykkC orykkD alone, gives rise to a broad specificity, multidrug-resistant phenotype including resistance to cationic, anionic, and neutral drugs.

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The Evolutionary Conservation of Escherichia coli Drug Efflux Pumps Supports Physiological Functions

Journal of Bacteriology ◽

10.1128/jb.00367-20 ◽

2020 ◽

Vol 202 (22) ◽

Cited By ~ 2

Author(s):

Tanisha Teelucksingh ◽

Laura K. Thompson ◽

Georgina Cox

Keyword(s):

Escherichia Coli ◽

Efflux Pump ◽

Efflux Pumps ◽

Evolutionary Conservation ◽

Drug Efflux ◽

Physiological Functions ◽

Content Type ◽

Bacterial Physiology ◽

E Coli ◽

Drug Efflux Pumps

ABSTRACT Bacteria harness an impressive repertoire of resistance mechanisms to evade the inhibitory action of antibiotics. One such mechanism involves efflux pump-mediated extrusion of drugs from the bacterial cell, which significantly contributes to multidrug resistance. Intriguingly, most drug efflux pumps are chromosomally encoded components of the intrinsic antibiotic resistome. In addition, in terms of xenobiotic detoxification, bacterial efflux systems often exhibit significant levels of functional redundancy. Efflux pumps are also considered to be highly conserved; however, the extent of conservation in many bacterial species has not been reported and the majority of genes that encode efflux pumps appear to be dispensable for growth. These observations, in combination with an increasing body of experimental evidence, imply alternative roles in bacterial physiology. Indeed, the ability of efflux pumps to facilitate antibiotic resistance could be a fortuitous by-product of ancient physiological functions. Using Escherichia coli as a model organism, we here evaluated the evolutionary conservation of drug efflux pumps and we provide phylogenetic analysis of the major efflux families. We show the E. coli drug efflux system has remained relatively stable and the majority (∼80%) of pumps are encoded in the core genome. This analysis further supports the importance of drug efflux pumps in E. coli physiology. In this review, we also provide an update on the roles of drug efflux pumps in the detoxification of endogenously synthesized substrates and pH homeostasis. Overall, gaining insight into drug efflux pump conservation, common evolutionary ancestors, and physiological functions could enable strategies to combat these intrinsic and ancient elements.

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