C16-ceramide and sphingosine 1-phosphate/S1PR2 have opposite effects on cell growth through mTOR signaling pathway regulation
- 주제(키워드) mTOR signaling , breast cancer , ceramide synthase , sphingosine-1-phosphate , sphingosine-1-phosphate receptor
- 주제(기타) Oncology
- 설명문(일반) [Kim, Min Hee; Lee, Eun-Ji; Park, Woo-Jae] Gachon Univ, Coll Med, Dept Biochem, 155 Gaetberllo, Incheon 21999, South Korea; [Park, Joo-Won; Shin, Sun-Hye; Ahn, Jung-Hyuck] Ewha Womans Univ, Coll Med, Dept Biochem, Seoul 07985, South Korea; [Kim, Shin] Keimyung Univ, Sch Med, Dept Immunol, Daegu 42601, South Korea; [Jung, Yunjae] Gachon Univ, Coll Med, Dept Microbiol, Incheon 21999, South Korea; [Jung, Yunjae; Park, Woo-Jae] Gachon Univ, GAIHST, Dept Hlth Sci & Technol, Incheon 21999, South Korea; [Park, Inkeun] Gachon Univ, Gil Med Ctr, Dept Internal Med, Div Med Oncol, 774 Namdongdaelo, Incheon 21565, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 SPANDIDOS PUBL LTD
- 발행년도 2018
- URI http://www.dcollection.net/handler/ewha/000000156363
- 본문언어 영어
- Published As http://dx.doi.org/10.3892/or.2018.6689
초록/요약
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.
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