INVESTIGADORES
VARONE Cecilia Laura
artículos
Título:
Leptin Is an Anti-Apoptotic Effector in Placental Cells Involving p53 Downregulation
Autor/es:
AYELÉN TORO; JULIETA L. MAYMÓ; FEDERICO IBARBALZ; ANTONIO PÉREZ-PÉREZ; BERNARDO MASKIN; ALICIA FALETTI; VÍCTOR SÁNCHEZ-MARGALET; CECILIA VARONE
Revista:
PLOS ONE
Editorial:
PUBLIC LIBRARY SCIENCE
Referencias:
Lugar: San Francisco; Año: 2014 vol. 9 p. 99187 - 99197
ISSN:
1932-6203
Resumen:
Leptin, a peripheral signal synthetized by the adipocyte to regulate energy metabolism, can also be produced by placenta,
where it may work as an autocrine hormone. We have previously demonstrated that leptin promotes proliferation and
survival of trophoblastic cells. In the present work, we aimed to study the molecular mechanisms that mediate the survival
effect of leptin in placenta. We used the human placenta choriocarcinoma BeWo and first trimester Swan-71 cell lines, as
well as human placental explants. We tested the late phase of apoptosis, triggered by serum deprivation, by studying the
activation of Caspase-3 and DNA fragmentation. Recombinant human leptin added to BeWo cell line and human placental
explants, showed a decrease on Caspase-3 activation. These effects were dose dependent. Maximal effect was achieved at
250 ng leptin/ml. Moreover, inhibition of endogenous leptin expression with 2 mM of an antisense oligonucleotide, reversed
Caspase-3 diminution. We also found that the cleavage of Poly [ADP-ribose] polymerase-1 (PARP-1) was diminished in the
presence of leptin. We analyzed the presence of low DNA fragments, products from apoptotic DNA cleavage. Placental
explants cultivated in the absence of serum in the culture media increased the apoptotic cleavage of DNA and this effect
was prevented by the addition of 100 ng leptin/ml. Taken together these results reinforce the survival effect exerted by
leptin on placental cells. To improve the understanding of leptin mechanism in regulating the process of apoptosis we
determined the expression of different intermediaries in the apoptosis cascade. We found that under serum deprivation
conditions, leptin increased the anti-apoptotic BCL-2 protein expression, while downregulated the pro-apoptotic BAX and
BID proteins expression in Swan-71 cells and placental explants. In both models leptin augmented BCL-2/BAX ratio.
Moreover we have demonstrated that p53, one of the key cell cycle-signaling proteins, is downregulated in the presence of
leptin under serum deprivation. On the other hand, we determined that leptin reduced the phosphorylation of Ser-46 p53
that plays a pivotal role for apoptotic signaling by p53. Our data suggest that the observed anti-apoptotic effect of leptin in
placenta is in part mediated by the p53 pathway. In conclusion, we provide evidence that demonstrates that leptin is a
trophic factor for trophoblastic cells.