유방암세포에서 Phytosphingosine의 EGF 수용체 저해를 통한 상피간엽이행 조절

Abstract

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. Even though D-ribophytosphingosine (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, I first time investigated 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. The PHS-mediated inhibition of EMT was validated by changes in several EMT marker and regulators. It was found that PHS-based inhibition of EMT was attributable by the downregulation of the EGFR/JAK1/STAT3 signaling axis, as validated by immunoprecipitation assays and breast tumorigenesis mice models. Together, these findings strongly uncover a mechanism that PHS inhibits the metastatic ability of breast cancer by blocking EGFR phosphorylation and its downstream signaling node, providing a rationale for breast cancer therapies during tumor relapse.