Phorbol ester-induced apoptosis in prostate cancer cells via autocrine activation of the extrinsic apoptotic cascade -: A key role for protein kinase Cδ

It is well established that activation of protein kinase C (PKC) by phorbol esters promotes apoptosis in androgen-dependent prostate cancer cells. However, there is limited information regarding the cellular mechanisms involved in this effect. In this report we identified a novel autocrine pro-apoptotic loop triggered by PKC delta activation in prostate cancer cells that is mediated by death receptor ligands. The apoptotic effect of phorbol 12-myristate 13-acetate in LNCaP cells was impaired by inhibition or depletion of tumor necrosis factor alpha-converting enzyme, the enzyme responsible for tumor necrosis factor alpha(TNF alpha) shedding. Moreover, the apoptogenic effect of conditioned medium collected after phorbol 12-myristate 13-acetate treatment could be inhibited by blocking antibodies against TNF alpha and tumor necrosis factor-related apoptosisinducing ligand (TRAIL), but not FasL, as well as by RNA interference depletion of TNF alpha and TRAIL receptors. Moreover, depletion or inhibition of death receptor downstream effectors, including caspase-8, FADD, p38 MAPK, and JNK, significantly reduced the apoptogenic effect of the conditioned medium. PKC delta played a major role in this autocrine loop, both in the secretion of autocrine factors as well as a downstream effector. Taken together, our results demonstrate that activation of PKC delta in prostate cancer cells causes apoptosis via the release of death receptor ligands and the activation of the extrinsic apoptotic cascade.