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
1946 syntynyt Tampereella
Ylioppilastutkinto 1964 Lempäälä
Lääketietaan kandidaatti 1966 Turun yliopisto
Lääketieteen lisensiaatti 1972 Turun Yliopisto
Dietetiikan opiskelu 1998 - 2001 Göteborgin Yliopisto
Eläkkeelle 2010
Inga kommentarer:
Skicka en kommentar