C16-ceramide and sphingosine 1-phosphate/S1PR2 have opposite effects on cell growth through mTOR signaling pathway regulation

Min Hee Kim, Joo Won Park, Eun Ji Lee, Shin Kim, Sun Hye Shin, Jung Hyuck Ahn, Yunjae Jung, Inkeun Park, Woo Jae Park

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Recently, sphingolipid derivatives, such as ceramide and sphingosine-1-phosphate (S1P), have emerged as key modulators in apoptotic cell death and cell proliferation. This study aimed to clarify the underlying signaling pathways of ceramide and S1P involved in breast cancer cell proliferation. Ceramide acyl chain length is determined by six mammalian ceramide synthases (CerS). We overexpressed CerS1 to 6 in MCF-7 cells to examine whether ceramide signaling propagation varies as a function of acyl chain length. Among the six CerS, only CerS6 overexpression reduced phosphorylation of Akt, S6 kinase (S6K), and extracellular signal-regulated kinases (ERK) as shown by western blotting. In addition, CerS6 overexpression reduced MCF-7 cell proliferation. This effect was partially reversed by co-treatment with MHY1485, an activator of mammalian target of rapamycin (mTOR), demonstrating an important role for the mTOR pathway in the CerS6-mediated decrease in MCF-7 cell proliferation. ERK inhibition, but not Akt inhibition, along with mTOR inhibition synergistically reduced MCF-7 cell proliferation as measured by MTT assay. Notably, the expression of CerS6 and S1P receptor 2 (S1PR2), or CerS6 and sphingosine kinase 1 (SphK1), were negatively correlated according to the invasive breast carcinoma patient cohort in The Cancer Genome Atlas database. In addition, both SphK1 overexpression and S1P addition increased mTOR phosphorylation as shown by ELISA, while S1PR2 inhibition had the inverse effect. These data suggest that CerS6 and SphK1 regulate mTOR signaling in breast cancer cell proliferation. Moreover, mTOR activity can be regulated by the balance between S1P and C16-ceramide, which is generated by CerS6.

Original languageEnglish
Pages (from-to)2977-2987
Number of pages11
JournalOncology Reports
Issue number5
StatePublished - Nov 2018

Bibliographical note

Funding Information:
This work was supported by funding from the Gachon University Gil Medical Center (grant no. 2014-20) and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2015R1C1A1A0 1054452).

Publisher Copyright:
© 2018 Oncology Reports. All Rights Reserved.


  • Breast cancer
  • Ceramide synthase
  • MTOR signaling
  • Sphingosine-1-phosphate
  • Sphingosine-1-phosphate receptor


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