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Concentration-dependent effects of sodium cholate and deoxycholate bile salts on breast cancer cells proliferation and survival

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Abstract

Bile acids (BAs) are bioactive molecules that have potential therapeutic interest and their derived salts are used in several pharmaceutical systems. BAs have been associated with tumorigenesis of several tissues including the mammary tissue. Therefore, it is crucial to characterize their effects on cancer cells. The objective of this work was to analyse the molecular and cellular effects of the bile salts sodium cholate and sodium deoxycholate on epithelial breast cancer cell lines. Bile salts (BSs) effects over breast cancer cells viability and proliferation were assessed by MTS and BrdU assays, respectively. Activation of cell signaling mediators was determined by immunobloting. Microscopy was used to analyze cell migration, and cellular and nuclear morphology. Interference of membrane fluidity was studied by generalized polarization and fluorescence anisotropy. BSs preparations were characterized by transmission electron microscopy and dynamic light scattering. Sodium cholate and sodium deoxycholate had dual effects on cell viability, increasing it at the lower concentrations assessed and decreasing it at the highest ones. The increase of cell viability was associated with the promotion of AKT phosphorylation and cyclin D1 expression. High concentrations of bile salts induced apoptosis as well as sustained activation of p38 and AKT. In addition, they affected cell membrane fluidity but not significant effects on cell migration were observed. In conclusion, bile salts have concentration-dependent effects on breast cancer cells, promoting cell proliferation at physiological levels and being cytotoxic at supraphysiological ones. Their effects were associated with the activation of kinases involved in cell signalling.

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Data Availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Abbreviations

AKT:

Protein kinase B

BrdU:

Bromodeoxyuridine

ERK 1/2:

Extracellular signal-regulated protein kinases 1 and 2

FXRα:

Farnesoid X receptor alpha

GP:

Generalalized polarization

JNK:

Jun amino-terminal kinase

MAPKS:

Mitogen-activated protein kinases

MTS:

3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium

PARP:

Poly ADP-ribose polymerase

PI3K:

Phosphatidylinositide 3-kinases

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Funding

MM, DC, SV and LG are Career Investigators of CONICET. CF is supported by a fellowship from the National Interuniversity Council (CIN) and MB and TL are supported by a fellowship from the University of Buenos Aires. Support for these studies was provided by CONICET (PIP-320) and ANPCYT (PICT 2013–937) to LG, and by UBA 20020130200005BA to LG and 20020130100195BA to SV. The funding sources had no involvement in the conduct of the research and/or preparation of the article.

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Authors and Affiliations

  1. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina

    Yamila B. Gándola, Marcela A. Moretton, Diego A. Chiapetta, Sandra V. Verstraeten & Lorena González

  2. Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 (1113), Buenos Aires, Argentina

    Yamila B. Gándola, Camila Fontana, Mariana A. Bojorge, Tania T. Luschnat, Sandra V. Verstraeten & Lorena González

  3. Facultad de Farmacia y Bioquímica, Departamento de Tecnología Farmacéutica, Universidad de Buenos Aires, Buenos Aires, Argentina

    Marcela A. Moretton & Diego A. Chiapetta

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  1. Yamila B. Gándola
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Contributions

YG, LG: conceived or designed study, YG, MB, CF, MB, TL, SV, LG: performed research, YG, CF, MM, DC, SV, LG: analyzed data, MM, DC, SV: contributed with new methods or models, YG, SV, LG: wrote the paper. All authors have read and approved the manuscript.

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Correspondence to Lorena González.

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11033_2020_5442_MOESM1_ESM.tif

Supplementary file1 (TIF 1138 kb)—Supplementary figure 1.BSs effects over MDA-MB-231 cells resemble those described in the MCF-7 cells. MDA-MB-231 cells were incubated for 24 h in the presence of (A) 0.05-2 mM SC or (B) 0.025-1 mM SDC. After incubation, cell viability was evaluated, and results were expressed as the percentage of the value recorded in untreated control cells. Triplicates were run for each treatment. MDA-MB-231 cells were incubated with 2 mM SC (C) or 1 mM SDC (D) for different time periods (0-24 h), the activation and protein content of Akt, p38 and actin were determined by immunoblotting. Representative western blot are shown. MDA-MB-231 cells were incubated for 24 h in the presence of 2 mM SC or 1 mM SDC and PARP or caspase-3 cleavage analyzed by immunoblotting (E) Actin was used as loading control. Representative western blot are shown. MDA-MB-231 cells were incubated in the presence of 0.01 mM SC (F) or 0.005 mM SDC (G) and Akt activation and cyclin D1 expression were determined by immunoblotting. Representative western blots are shown.

11033_2020_5442_MOESM2_ESM.tif

Supplementary file2 (TIF 266 kb)—Supp. Fig. 2. Chemical structures and properties of the BSs investigated in this work. The optimization of (A) SC and (B) SDC chemical structures was performed by molecular mechanics (MM2) according to [67] using the routines available in ChemBio3D Ultra 11.0.1 (Cambridge Scientific Computing Inc.). (C) BS chemical properties. Pow: octanol/water partition coefficient. S: water solubility. PSA: polar surface area.

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Gándola, Y.B., Fontana, C., Bojorge, M.A. et al. Concentration-dependent effects of sodium cholate and deoxycholate bile salts on breast cancer cells proliferation and survival. Mol Biol Rep 47, 3521–3539 (2020). https://doi.org/10.1007/s11033-020-05442-2

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