IFN-alpha enhances TNF-alpha-induced apoptosis through down-regulation of c-Myc protein expression in HL-60 cells.

Abstract

We examined the effect of interferon-alpha (IFN-alpha) in combination with tumor necrosis factor-a (TNF-alpha) on growth, differentiation and apoptosis in HL-60 human myeloid leukemia cells. IFN-alpha inhibited cell growth and induced apoptosis, but not differentiation, in HL-60 cells. IFN-alpha enhanced TNF-alpha-induced apoptosis. We also investigated the expression of c-Myc and Bcl-2 oncoproteins, which are implicated in the survival or death of a cell. The levels of c-Myc protein expression were not changed by IFN-alpha alone at 24hrs of treatment, but were down-regulated at 72 hrs, accompanied by the appearance of apoptotic cells. While, IFN-alpha did not affect the level of Bcl-2 protein expression during this cultivation time. Interestingly, a combination treatment of IFN-alpha with TNF-alpha showed a greater decrease of c-Myc expression than TNF-a alone at 24hrs. Whereas, IFN-alpha did not significantly modulate Bcl-2 expression levels which were down-regulated by TNF-alpha. Therefore, the enhancement of TNF-alpha-induced apoptosis by IFN-a might be closely associated with the greater down-regulation of c-Myc protein, rather than Bcl-2. In contrast, with rapid down-regulation of c-Myc expression caused by TNF-alpha, IFN-alpha down-regulated c-Myc rather late (at 72 hrs), suggesting that both cytokines have a distinct pathway regulating c-Myc protein expression. However, the enhancement of apoptosis in the combination treatment would suggest the presence of a common signaling pathway for induction of apoptosis at down-stream of c-Myc.

• Authors: A Nakashima, S Kumakura, S Mishima, H Ishikura, S Kobayashi
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 24 Issue 3 Pg. 447-56 (Sep 2005) ISSN: 0392-9078 [Print] England
• PMID: 16270532 (Publication Type: Journal Article)

Chemical References

• DNA, Neoplasm
• Interferon-alpha
• Proto-Oncogene Proteins c-bcl-2
• Proto-Oncogene Proteins c-myc
• Tumor Necrosis Factor-alpha

Topics

• Apoptosis (drug effects)
• Cell Differentiation (drug effects)
• DNA, Neoplasm (metabolism)
• Down-Regulation (drug effects)
• Flow Cytometry
• HL-60 Cells
• Humans
• Interferon-alpha (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)