CEFYBO   02669
CENTRO DE ESTUDIOS FARMACOLOGICOS Y BOTANICOS
Unidad Ejecutora - UE
artículos
Título:
Induction of apoptosis in T lymphoma cells by long-term treatment with thyroid hormones involves PKC zetha nitration by inducible nitric oxide synthase
Autor/es:
BARREIRO ARCOS M.L.; STERLE H.A.; VERCELLI C.; VALLI E.; CAYROL M.F.; KLECHA A.J.; PAULAZO M.A.; DIAZ FLAQUÉ C.; FRANCHI A.M.; CREMASCHI G.A.
Revista:
APOPTOSIS
Editorial:
SPRINGER
Referencias:
Año: 2012
ISSN:
1360-8185
Resumen:
ABSTRACT  Thyroid hormones are important regulators of cell physiology, leading to cell proliferation, differentiation or apoptosis, depending on cell type. On T lymphocytes they are able to induce proliferation at short-term cultures. Here, the effect of long-term culturing T lymphoma cells with thyroxine (T4) on the balance of proliferation and apoptosis and the intermediate participants were studied. From the fifth day of culture, T4 affected this balance inhibiting proliferation in a time-dependent manner. This was related to apoptosis induction, as characterized by nuclear morphological changes, DNA fragmentation, and annexin V-FITC / Propidium Iodide co-staining. Also, exacerbated increases of iNOS gene and protein levels, as well as of enzyme activity were observed. Additionally, these effects were accompanied by an increment of hydrogen peroxide and superoxide anion production, thus leading to mitochondrial membrane depolarization and decreased reduced glutathione levels. The imbalance between oxidants and antioxidants species increased the content of free radicals, leading to the nitration of proteins including PKCz, an isoenzyme essential for this lymphoma cell division and survival. Also, evidence of nitrated-PKCz degradation via proteasome is here provided. These results suggest that long-term culture of T lymphoma cells with T4 induces apoptosis by increasing the content of free radicals as a result of both iNOS augmented activity and the loss of mitochondrial function. These oxidant species lead to the nitration of proteins involved in cell viability, promoting its degradation by the proteasome. The implication of these mechanisms in the modulation of tumour T lymphoma growth in vivo is discussed as well.