The early phase of programmed cell death in caco-2 intestinal cells exposed to PTH

CALVO, NATALIA; GENTILI, CLAUDIA; RUSSO DE BOLAND, ANA

JOURNAL OF CELLULAR BIOCHEMISTRY

Wiley-Liss Inc.

Lugar: USA; Año: 2008 vol. 105 p. 989 - 997

0730-2312

The regulation of apoptosis is critical for ensuring the homeostasis of an organism. As such, the cell has derived various mechanismsto precisely control the balance between survival and apoptotic signaling. Parathyroid hormone (PTH) function as a major mediator ofbone remodeling and as an essential regulator of calcium homeostasis. Depending on the cell type involved, PTH also inhibits or promotesthe apoptosis. In a previous work we found that PTH promotes the apoptosis of human Caco-2 intestinal cells. In the current study, wedemonstrate, for the first time, that stimulation of Caco-2 cells with PTH (10-8 M) results in the dephosphorylation and translocation of proapoptoticprotein Bad from the cytosol to mitochondria and release of cytochrome c and Smac/Diablo. The hormone also triggersmitochondria cellular distribution to the perinuclear region, morphological features consistent with apoptosis. PTH increases the enzymaticactivity of caspase-3 (48 h) that is also evidenced from the appearance of its cleaved fragments in western blot experiments. Moreover, activecaspase-3 is present in nucleus after PTH treatment. In addition, a caspase-3 substrate, poly (ADP-ribose) polymerase (PARP), is degraded by48 h of PTH treatment. Taken together, our results suggest that, in Caco-2 cells, the induction of apoptosis in response to PTH is mediatedby translocation of mitochondria to the perinuclear region, dephosphorylation of Akt, dephosphorylation of Bad and its movement to themitochondria and subsequent release of cytochrome c and Smac/Diablo which result in activation of downstream caspase-3.