Mecanismo de acción de PTH en células de adenocarcinoma de colon humano

Abstract

Parathyroid hormone (PTH) besides acting on the classical target tissues, bone and kidney, regulates important physiological functions in the intestine. In intestinal cells, PTH, after binding to its receptor (PTHR1) at the plasma membrane, activates cAMP/PKA, DAG/IP3/PKC signal transduction pathways, MAP kinases cascades and regulates intracellular Ca2+ concentration. In the intestinal cell line Caco-2, derived from human colorectal adenocarcinoma, PTH treatment in serum free medium diminished the number of viable cells. Moreover, the hormone induced disruption of actin filaments with changes to cellular shape, alteration of cell-to-cell junctions, externalization of membrane phosphatidylserine, mitochondrial cellular distribution to the perinuclear region, chromatin condensation and DNA fragmentation of the nucleus, which are morphological features consistent with apoptosis. In addition, the hormone induces the dephosphorylation of pro-apoptotic protein Bad, its dissociation of 14-3-3 protein and its translocation to the mitochondria with the subsequent release of cytochrome c and Smac/Diablo to the cytosol which resulted in activation of downstream caspase-3 and degradation of its substrate PARP. In these cells, PTH, besides activating the mitochondrial pathway of apoptosis, inhibits AKT survival pathway via the serine/threonine phosphatase PP2A and cAMP. Knowledge of the molecular mechanisms involved in apoptosis of intestinal cells could be used to generate pro-apoptotic drugs in the treatment of human colon cancer.