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BSA-bounded p-cresyl sulfate potentiates the malignancy of bladder carcinoma by triggering cell migration and EMT through the ROS/Src/FAK signaling pathway

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Abstract

Para-cresyl sulfate (P-CS), a major uremic toxin derived from the metabolites of tyrosine and phenylalanine through liver, existed in the blood of patients with chronic kidney disease (CKD). CKD increases the malignancy in bladder cancers; however, effects of P-CS on bladder cancers are not fully understood. P-CS is conjugated with BSA physiologically, and this study aims to investigate the effects and possible underlying mechanisms of BSA-bounded P-CS on human bladder cancer cells. With P-CS treatment, the intracellular ROS increased in bladder cancer cells. ROS then triggered epithelial-mesenchymal transition (EMT), stress fiber redistribution, and cell migration. With specific inhibitors, the key signals regulating P-CS-treated migration are Src and FAK. This study provided a clinical clue that patients with higher serum P-CS have a higher risk of malignant urothelial carcinomas, and a regulatory pathway of how P-CS regulates bladder cancer migration.

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Acknowledgements

We would like to thank the Kureha Corporation (Japan) for providing P-CS. We would like to acknowledge the financial support of Far Eastern Memorial Hospital and Ministry of Science and Technology which the grant numbers are FEMH–2014–D-005 and 104-2320-B-002-062-MY3. We would like to acknowledge the service provided by the Flow Cytometric Analyzing and Sorting Core of the First Core Laboratory, National Taiwan University College of Medicine. We also thank the staff of the imaging core at the First Core Labs, National Taiwan University College of Medicine, for technical assistances. All authors have read the journal’s authorship statement.

Contract grant sponsor: Far Eastern Memorial Hospital (FEMH–2014–D-005), Ministry of Science and Technology (104-2320-B-002-062-MY3).

Funding

This work was supported by Far Eastern Memorial Hospital (grant number FEMH–2014–D-005) and Ministry of Science and Technology in Taiwan (grant number 104-2320-B-002-062-MY3).

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Authors and Affiliations

  1. Division of Nephrology, Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan

    Yu-Sen Peng

  2. Department of Electrical Engineering, Yuan-Ze University, Taoyuan City, Taiwan

    Yu-Sen Peng

  3. Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, 1-1 Jen-Ai Road, 10051, Taipei, Taiwan

    Jhih-Pu Syu, Sheng-De Wang, Pie-Chun Pan & Hsiu-Ni Kung

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YSP and HSK designed the experiments and prepared the manuscript. SDW, JPS, and PCP performed the experiments and analyzed the results. All authors revised the manuscript and gave approval of the manuscript.

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Supplementary Figure 1

(Upper panel) The cell viability was analyzed by MTT assay with 48-h P-CS treatment. Mean ± SEM. (Lower panel) Cells migrated through transwell membranes with 48-h P-CS (20 μg/ml) treatment. Scale, 100 μm. (PDF 61 kb)

Supplementary Figure 2

The actin-phalloidin staining of cells with 24 h treatment of DMSO (CTL) and P-CS (20 μg/ml). The left panel showed the high cell density while the right panel showed the low cell density. (PDF 2907 kb)

Supplementary Figure 3

(A–C) The quantification of proteins from western blot analysis of Fig. 5C, E, and F. *p < 0.05 compared to CTL, #p < 0.05 compared to P-CS. (PDF 86 kb)

Supplementary Figure 4

The H2O2 measured by flow cytometry with DCFHDA staining in 5637 and BFTC905 cells. Cells were treated with 24-h P-CS and 1-h DTT (0.5 μM) pretreatment. (PDF 874 kb)

Supplementary Figure 5

The protein expressions of p-Src and p-FAK under 15-min P-CS administration with or without 1 h DTT (0.5 μM) pretreatment in 5637 and BFTC905 cells. (PDF 292 kb)

Supplementary Figure 6

Scrape wound healing assay showed the cell migration in 5637 and BFTC905 cells with treatment of P-CS (20 μg/ml) and ROS chelators (0.5 μM DTT and 1 μM NAC). Scale bar: 100 μm. *p < 0.05, **p < 0.01 compared to CTL, and #p < 0.05 compared to P-CS. (PDF 30711 kb)

Supplementary Figure 7

All the results of western blots. (PDF 1605 kb)

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Peng, YS., Syu, JP., Wang, SD. et al. BSA-bounded p-cresyl sulfate potentiates the malignancy of bladder carcinoma by triggering cell migration and EMT through the ROS/Src/FAK signaling pathway. Cell Biol Toxicol 36, 287–300 (2020). https://doi.org/10.1007/s10565-019-09509-0

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