4.3 Article

Phytosphingosine exhibits an anti-epithelial-mesenchymal transition function by the inhibition of EGFR signaling in human breast cancer cells

Journal

ONCOTARGET
Volume 8, Issue 44, Pages 77794-77808

Publisher

IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.20783

Keywords

phytosphingosine; epithelial-mesenchymal transition; cancer stem cells; epidermal growth factor receptor

Funding

  1. National Research Foundation (NRF)
  2. Ministry of Science, ICT and Future Planning, Korean Government [NRF-2015M2A2A7A01044998]
  3. Korea Institute of Radiological and Medical Sciences [1711045557/1711045538/1711045554/50531-2017]
  4. National Research Foundation of Korea [2015M2A2A7A01044998] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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The lack of effective anti-metastatic drugs for the eradication of breast cancer stem cells within tumors, which are often resistant to chemotherapy and radiotherapy, creates a major obstacle during metastatic breast cancer therapy. Although D-ribo-phytosphingosine (PHS) is well known to activate protein kinase (MAPK)-mediated apoptosis, its possible role towards the metastasis signaling mechanisms underlying the epithelial-mesenchymal transition (EMT) remains largely unknown. In this report, we investigate the anti-metastatic potential of the natural sphingolipid PHS for the targeting of breast cancer cells as well as breast stem-like cells in vitro. We showed that PHS led to suppression of migratory potential, spheroid formation, CD44(high)/CD24(low) subpopulation as well as stem cell-and EMT-associated protein expression in basal type highly malignant breast cancer cell lines. In addition, PHS-based inhibition of EMT was attributable to the downregulation of the EGFR/JAK1/STAT3 signaling axis, as validated by immunoprecipitation assays and breast tumorigenesis mice models. This study demonstrate that PHS can target metastatic tumors with dual specificity (EMT and cancer stem-like cells) and therefore may be serve as a promising candidate for breast cancer treatments.

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