INVESTIGADORES
PESCIO Lucila Gisele
congresos y reuniones científicas
Título:
Inhibition of SK1 stimulates sphingolipids de novo synthesis enhancing ceramida accumulation.
Autor/es:
LEOCATA NIETO F; PESCIO L; SALAMA F; STERIN-SPEZIALE N
Lugar:
Rosario , Santa Fe, Argentina
Reunión:
Congreso; XLII Annual Meeting of the Argentine Society for Biochemistry and Molecular Biology Research; 2006
Institución organizadora:
SAIB
Resumen:
We reported that Sphingosine Kinase 1 (SK1) inhibition with
D,L,-threo-dihydrosphingosine (tDHS), in subconfluent MDCK
cultures, causes cell number and viability decrease (33% and
16%). Incubation with 14C-palmitic acid (PA) shows an increase
of de novo synthesized Ceramide (Cer) (39% of labeling
sphingolipids (SLs) vs. 26% in control). Since Cer synthesis
inhibition with Fumonisine B1 attenuates the apoptotic effect, we
concluded that such an effect is due to Cer accumulation. On the
other hand, reduction of SK1 expression by using SK1-siRNA,
also decreases both cell number and viability (60% and 85%)
and raises Cer synthesis (43% vs. 35%). Labeling assays with
14C-PA show that both tDHS and siRNA increase total 14C-PASLs
by 60% and 43%, respectively. To evaluate if the increase in
total SLs synthesis raises Cer production thus contributing with
SK1 inhibition effect on cell viability, we studied serine-palmitoyl
transferase (SPT), which catalyzes the rate-limiting step of de
novo synthesis, by treating MDCK cells with SPT inhibitor, Lcicloserine,
plus tDHS. We found attenuation in tDHS effect: a
raise in cell number and viability and a decrease in Cer
production. These results indicate that SK1 inhibition abrogates a
negative control on SLs de novo synthesis (possibly on SPT
activity) thus enhancing Cer production, which could not be
clearing by its conversion to Sphingosine-1P.