Potentiation of tumour apoptosis by human growth hormone via glutathione production and decreased NF-kappaB activity.
In addition to its primary role as growth factor, human growth hormone (hGH) can also participate in cell survival, as already documented by its protective effect on human monocytes or human promyelocytic leukaemia U937 cells exposed to a Fas-mediated cell death signal. However, despite similarities in the molecular events following Fas and TNF-alpha receptor engagement, we report that U937 cells, genetically engineered to constitutively produce hGH, were made more sensitive to TNF-alpha-induced apoptosis than parental cells. This was due to overproduction of the antioxidant glutathione, which decreased the nuclear factor (NF)-kappaB activity known to control the expression of survival genes. These findings were confirmed in vivo, in nude mice bearing U937 tumours coinjected with recombinant hGH and the NF-kappaB -inducing anticancer drug daunorubicin, to avoid the in vivo toxicity of TNF-alpha. This study therefore highlights one of the various properties of hGH that may have potential clinical implications.
Cherbonnier
C
C
INSERM U542/Paris XI University, Villejuif Cedex, France.
Déas
O
O
Carvalho
G
G
Vassal
G
G
Dürrbach
A
A
Haeffner
A
A
Charpentier
B
B
Bénard
J
J
Hirsch
F
F
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D003630:Daunorubicin / Q000494:pharmacology; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D005978:Glutathione / Q000096:biosynthesis*; D019382:Human Growth Hormone / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000473:pathology* / Q000517:prevention & control; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015996:Survival Rate; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020298:U937 Cells / Q000637:transplantation; D019014:fas Receptor / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D016328:NF-kappa B; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D019382:Human Growth Hormone; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D005978:Glutathione; D003630:Daunorubicin