The inhibition of apoptosis by alpha-fetoprotein (AFP) and the role of AFP receptors in anti-cellular senescence.
The mechanism of paradoxical growth enhancement by alpha-fetoprotein (AFP), a nonmitogenic factor, was explored in HL-60 cells using novel AFP agonists, the 167H.1 and 167H.4 monoclonal antibodies (MAbs) to AFP receptor (AFPr) isoforms. The conditions underwhich AFP led to increases in thymidine incorporation were found to promote activation induced cell death (AICD) associated with adherence in 96 well plates. The ensuing death was judged to be apoptosis based on morphology, shrinkage of dying cells, inducibility, reversibility, a sensitivity to levels of FCS, kinetics, DNA fragmentation pattern and internal program (passage number) of the cells investigated. Both AFP and the 167H.1 MAb but not the 167H.4 MAb blocked the induction of cell death under these conditions indicating apparent growth enhancement by AFP relates to the abrogation of cell death and not that AFP contains bona fide growth factor-like activity. We additionally report that HL-60 cells spontaneously senescence during normal propagation in vitro which correlated with an increased susceptibility to and earlier kinetics of AICD. In substantiation of this was the correlation of the loss of expression of the AFPr with increasing passage number and the induction of AICD. Overall, our findings lend further support to the recent proposals that AFP by binding to AFP receptors may block cellular senescence and that there may be differential expression of AFPr isoforms related to commitment (167H.1 reactive) or resistance (167H.4 reactive) of cells to apoptosis/programmed cell death (PCD).
Laderoute
M P
MP
Department of Immunology, University of Alberta, Edmonton, Canada.
Pilarski
L M
LM
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002448:Cell Adhesion; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016922:Cellular Senescence; D004273:DNA, Neoplasm / Q000032:analysis; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D018000:Receptors, Peptide / Q000276:immunology / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000509:alpha-Fetoproteins / Q000276:immunology / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D004273:DNA, Neoplasm; D018000:Receptors, Peptide; D000509:alpha-Fetoproteins; C042144:alpha-fetoprotein receptor, human