Involvement of protein kinase C delta (PKCdelta) in phorbol ester-induced apoptosis in LNCaP prostate cancer cells. Lack of proteolytic cleavage of PKCdelta.

Phorbol esters, the activators of protein kinase C (PKC), induce apoptosis in androgen-sensitive LNCaP prostate cancer cells. The role of individual PKC isozymes as mediators of this effect has not been thoroughly examined to date. To study the involvement of the novel isozyme PKCdelta, we used a replication-deficient adenovirus (PKCdeltaAdV), which allowed for a tightly controlled expression of PKCdelta in LNCaP cells. A significant reduction in cell number was observed after infection of LNCaP cells with PKCdeltaAdV. Overexpression of PKCdelta markedly enhanced the apoptotic effect of phorbol 12-myristate 13-acetate in LNCaP cells. PKCdelta-mediated apoptosis was substantially reduced by the pan-caspase inhibitor z-VAD and by Bcl-2 overexpression. Importantly, and contrary to other cell types, PKCdelta-mediated apoptosis does not involve its proteolytic cleavage by caspase-3, suggesting that allosteric activation of PKCdelta is sufficient to trigger apoptosis in LNCaP cells. In addition, phorbol ester-induced apoptosis was blocked by a kinase-deficient mutant of PKCdelta, supporting the concept that PKCdelta plays an important role in the regulation of apoptotic cell death in LNCaP prostate cancer cells.

Cardiovascular tests of autonomic function and sympathetic skin responses in patients with major depression.

To assess the function of the autonomic nervous system in major depression, a series of cardiovascular tests, together with the recording of sympathetic skin response, were performed in 18 depressed patients (melancholic type, DSM-III-R criteria) and in 18 healthy control subjects. Depressed patients showed significantly poorer performance in Valsalva's, deep breathing, and lying to standing manoeuvres than controls, indicating an impairment of parasympathetic function. Depressed patients developed a significantly larger sympathetic skin response than controls during the lying to standing and hand grip manoeuvres, whereas cardiovascular sympathetic performance (as assessed by the responses to hand grip, cold, mental arithmetic, explosive sound, or hyperventilation) was similar in both groups. The results are compatible with the view that a diminished parasympathetic reactivity, and presumably an increased sympathetic reactivity, occur in patients with major depression.