Salinomycin induces selective cytotoxicity to MCF-7 mammosphere cells through targeting the Hedgehog signaling pathway

  • Authors:
    • Ying-Zi Fu
    • Yuan-Yuan Yan
    • Miao He
    • Qing-Huan Xiao
    • Wei-Fan Yao
    • Lin Zhao
    • Hui-Zhe Wu
    • Zhao-Jin Yu
    • Ming-Yi Zhou
    • Mu-Tian Lv
    • Shan-Shan Zhang
    • Jian-Jun Chen
    • Min-Jie Wei
  • View Affiliations

  • Published online on: November 17, 2015     https://doi.org/10.3892/or.2015.4434
  • Pages: 912-922
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Abstract

Breast cancer stem cells (BCSCs) are believed to be responsible for tumor chemoresistance, recurrence, and metastasis formation. Salinomycin (SAL), a carboxylic polyether ionophore, has been reported to act as a selective breast CSC inhibitor. However, the molecular mechanisms underlying SAL-induced cytotoxicity on BCSCs remain unclear. The Hedgehog (Hh) signaling pathway plays an important role in CSC maintenance and carcinogenesis. Here, we investigated whether SAL induces cytotoxicity on BCSCs through targeting Hh pathway. In the present study, we cultured breast cancer MCF-7 cells in suspension in serum-free medium to obtain breast CSC-enriched MCF-7 mammospheres (MCF-7 MS). MCF-7 MS cells possessed typical BCSC properties, such as CD44+CD24-/low phenotype, high expression of OCT4 (a stem cell marker), increased colony-forming ability, strong migration and invasion capabilities, differentiation potential, and strong tumorigenicity in xenografted mice. SAL exhibited selective cytotoxicity to MCF-7 MS cells relative to MCF-7 cells. The Hh pathway was highly activated in BCSC-enriched MCF-7 MS cells and SAL inhibited Hh signaling activation by downregulating the expression of critical components of the Hh pathway such as PTCH, SMO, Gli1, and Gli2, and subsequently repressing the expression of their essential downstream targets including C-myc, Bcl-2, and Snail (but not cyclin D1). Conversely, Shh-induced Hh signaling activation could largely reverse SAL-mediated inhibitory effects. These findings suggest that SAL-induced selective cytotoxicity against MCF-7 MS cells is associated with the inhibition of Hh signaling activation and the expression of downstream targets and the Hh pathway is an important player and a possible drug target in the pathogenesis of BCSCs.
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February-2016
Volume 35 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Fu Y, Yan Y, He M, Xiao Q, Yao W, Zhao L, Wu H, Yu Z, Zhou M, Lv M, Lv M, et al: Salinomycin induces selective cytotoxicity to MCF-7 mammosphere cells through targeting the Hedgehog signaling pathway. Oncol Rep 35: 912-922, 2016
APA
Fu, Y., Yan, Y., He, M., Xiao, Q., Yao, W., Zhao, L. ... Wei, M. (2016). Salinomycin induces selective cytotoxicity to MCF-7 mammosphere cells through targeting the Hedgehog signaling pathway. Oncology Reports, 35, 912-922. https://doi.org/10.3892/or.2015.4434
MLA
Fu, Y., Yan, Y., He, M., Xiao, Q., Yao, W., Zhao, L., Wu, H., Yu, Z., Zhou, M., Lv, M., Zhang, S., Chen, J., Wei, M."Salinomycin induces selective cytotoxicity to MCF-7 mammosphere cells through targeting the Hedgehog signaling pathway". Oncology Reports 35.2 (2016): 912-922.
Chicago
Fu, Y., Yan, Y., He, M., Xiao, Q., Yao, W., Zhao, L., Wu, H., Yu, Z., Zhou, M., Lv, M., Zhang, S., Chen, J., Wei, M."Salinomycin induces selective cytotoxicity to MCF-7 mammosphere cells through targeting the Hedgehog signaling pathway". Oncology Reports 35, no. 2 (2016): 912-922. https://doi.org/10.3892/or.2015.4434