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Potentiation of tumour apoptosis by human growth hormone via glutathione production and decreased NF-kappaB activity.

Cherbonnier C, Déas O, Carvalho G, Vassal G, Dürrbach A, Haeffner A, Charpentier B, Bénard J, Hirsch F - Br. J. Cancer (2003)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: INSERM U542/Paris XI University, Villejuif Cedex, France.

ABSTRACT
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.

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Related in: MedlinePlus

Effect of hGH on IκB degradation. Whole-cell extracts from the indicated cell lines stimulated with TNF-α (10 ng ml−1) for 0–120 min were subjected to Western blotting using anti-IκB Abs under the conditions described in Materials and Methods.
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fig3: Effect of hGH on IκB degradation. Whole-cell extracts from the indicated cell lines stimulated with TNF-α (10 ng ml−1) for 0–120 min were subjected to Western blotting using anti-IκB Abs under the conditions described in Materials and Methods.

Mentions: Intracellular localisation of NF-κB can be closely monitored by its interaction with members of the IκB family. In response to various stimuli, IκB undergoes proteolytic degradation, which allows nuclear translocation of NF-κB leading to gene activation (Baeuerle and Baltimore, 1988 #733). To determine whether the decreased activation of NF-κB observed in hGH-treated cells was due to a modulation of Iκ degradation, we performed Western blot analyses on whole-cell extracts from our cell lines. After TNF-α exposure, degradation of κB was observed in U937-Neo cells, while no degradation was detected in U937-hGH cells, even after incubation for 2 h (Figure 3Figure 3


Potentiation of tumour apoptosis by human growth hormone via glutathione production and decreased NF-kappaB activity.

Cherbonnier C, Déas O, Carvalho G, Vassal G, Dürrbach A, Haeffner A, Charpentier B, Bénard J, Hirsch F - Br. J. Cancer (2003)

Effect of hGH on IκB degradation. Whole-cell extracts from the indicated cell lines stimulated with TNF-α (10 ng ml−1) for 0–120 min were subjected to Western blotting using anti-IκB Abs under the conditions described in Materials and Methods.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376966&req=5

fig3: Effect of hGH on IκB degradation. Whole-cell extracts from the indicated cell lines stimulated with TNF-α (10 ng ml−1) for 0–120 min were subjected to Western blotting using anti-IκB Abs under the conditions described in Materials and Methods.
Mentions: Intracellular localisation of NF-κB can be closely monitored by its interaction with members of the IκB family. In response to various stimuli, IκB undergoes proteolytic degradation, which allows nuclear translocation of NF-κB leading to gene activation (Baeuerle and Baltimore, 1988 #733). To determine whether the decreased activation of NF-κB observed in hGH-treated cells was due to a modulation of Iκ degradation, we performed Western blot analyses on whole-cell extracts from our cell lines. After TNF-α exposure, degradation of κB was observed in U937-Neo cells, while no degradation was detected in U937-hGH cells, even after incubation for 2 h (Figure 3Figure 3

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: INSERM U542/Paris XI University, Villejuif Cedex, France.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus