Autocrine regulation of TPA-induced apoptosis in monoblastic cell-line U-937: role for TNF-alpha, MnSOD and IL-6
Champelovier, P.; Richard, M.J.; Seigneurin, D.
Anticancer Research 20(1a): 451-458
2000
ISSN/ISBN: 0250-7005 PMID: 10769695 Document Number: 518902
The present studies were undertaken to analyse the factors regulating TPA-induced apoptosis. Treatment of the monoblastic U-937 cells with the phorbol ester, TPA, was found to induce apoptosis in two distinct phases. In phase I (from 0 to 72 hours following TPA induction), apoptotic cells appeared, despite the expression of high levels of the anti-apoptotic Bcl-2 protein. After 96 h. of TPA treatment (phase II), the percentage of apoptotic cells increased as did the cell differentiation stage. The first phase apoptotic response could be significantly reduced (70%) by treatment with anti-tumor necrosis factor-alpha (TNF-alpha) antibody. TNF-alpha protein required de novo RNA and protein synthesis and was found to be mediated by protein kinase and protein tyrosine kinases. Manganese superoxide dismutase (MnSOD) inhibited, whereas IL-6 increased TPA-induced apoptosis. These findings suggest that both TPA, via TNF-alpha synthesis, exerts its protective function intracellularly by inducing MnSOD production and IL-6 may be an effective adjunct to TNF-alpha in the clinic, increasing the antitumor potency of this cytokine.