Activation-induced cell death of aggressive histology lymphomas by CD40 stimulation: induction of bax.
CD40 is present on both normal and neoplastic B-lineage cells. CD40 stimulation of normal B cells has been shown to promote normal growth and differentiation, whereas aggressive histology B lymphomas are growth inhibited. The inhibition of neoplastic B-cell growth is believed to occur via activation-induced cell death in which stimuli that typically promote the growth of normal cells prevent the growth of their neoplastic counterparts. We show here that CD40 stimulation using either a soluble recombinant human CD40 ligand (srhCD40L) or anti-CD40 monoclonal antibody resulted in apoptosis of human Burkitt lymphoma cell lines. Additional studies examining the mechanism of CD40-mediated death revealed an increase in bax messenger RNA with a subsequent increase in Bax protein in the mitochondria of the treated cells. In vitro exposure of the cells to bax antisense oligonucleotides resulted in a significant decline in Bax protein levels and partial protection from CD40-mediated death, indicating that induction of Bax was at least one mechanism underlying this inhibitory effect of CD40 stimulation on lymphomas. When immunodeficient mice bearing Burkitt lymphoma were treated with srhCD40L, significant increases in survival were observed indicating a direct antitumor effect as a result of CD40 stimulation in vivo. Overall, these results demonstrate that CD40 ligation of aggressive histology B-lymphoma cells results in inhibition both in vitro and in vivo and thus may be of potential clinical use in their treatment.
Szocinski
Jamie L
JL
Laboratory of Leukocyte Biology,and SAIC-Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA.
Khaled
Annette R
AR
Hixon
Julie
J
Halverson
Douglas
D
Funakoshi
Satoshi
S
Fanslow
William C
WC
Boyd
Ann
A
Taub
Dennis D
DD
Durum
Scott K
SK
Siegall
Clay B
CB
Longo
Dan L
DL
Murphy
William J
WJ
D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism / Q000502:physiology*; D023201:CD40 Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D015996:Survival Rate; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494827:Bax protein, mouse; D019013:CD40 Antigens; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D023201:CD40 Ligand