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

Title
C16-ceramide and sphingosine 1-phosphate/S1PR2 have opposite effects on cell growth through mTOR signaling pathway regulation
Authors
Kim, Min HeePark, Joo-WonLee, Eun-JiKim, ShinShin, Sun-HyeAhn, Jung-HyuckJung, YunjaePark, InkeunPark, Woo-Jae
Ewha Authors
안정혁박주원김민혜
SCOPUS Author ID
안정혁scopus; 박주원scopus; 김민혜scopus
Issue Date
2018
Journal Title
ONCOLOGY REPORTS
ISSN
1021-335XJCR Link

1791-2431JCR Link
Citation
ONCOLOGY REPORTS vol. 40, no. 5, pp. 2977 - 2987
Keywords
mTOR signaling; breast cancer; ceramide synthase; sphingosine-1-phosphate; sphingosine-1-phosphate receptor
Publisher
SPANDIDOS PUBL LTD
Indexed
SCI; SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
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 MP 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 MP 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 MP 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 MP and C16-ceramide, which is generated by CerS6.
DOI
10.3892/or.2018.6689
Appears in Collections:
의과대학 > 의학과 > Journal papers
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