p44/42 MAP kinase-dependent regulation of catalase by autocrine human growth hormone protects human mammary carcinoma cells from oxidative stress-induced apoptosis.
Previous microarray expression analyses have indicated autocrine human growth hormone (hGH) regulation of genes involved in the oxidative stress response. Expression analysis of antioxidant enzymes revealed that autocrine hGH increased both the mRNA and protein levels of catalase, superoxide dismutase 1 (SOD1), glutathione peroxidase and glutamylcysteine synthetase but not that of SOD2. As a consequence, autocrine hGH increased the antioxidant capacity of mammary carcinoma cells and protected against oxidative stress-induced apoptosis. Catalase activity was increased by autocrine production of hGH in mammary carcinoma cells and a catalase inhibitor abrogated protection from oxidative stress afforded by autocrine hGH. Autocrine hGH transcriptionally regulated catalase gene expression in a p44/42 MAP kinase-dependent manner and inhibition of MEK concordantly abrogated the protective effect of autocrine hGH against oxidative stress-induced apoptosis. Given that increased cellular oxidative stress is a key effector mechanism of specific chemotherapeutic agents, we propose that antagonism of autocrine hGH will improve the efficacy of chemotherapeutic regimes utilized for human mammary carcinoma.
Zhu
Zhe
Z
Department of Medicine, National University of Singapore, 30 Medical Dr., Singapore 117609, Republic of Singapore. p.lobie@auckland.ac.nz
Mukhina
Svetlana
S
Zhu
Tao
T
Mertani
Hichem C
HC
Lee
Kok-Onn
KO
Lobie
Peter E
PE
D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002374:Catalase / Q000235:genetics*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D019382:Human Growth Hormone / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D050807:ets-Domain Protein Elk-1
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D019382:Human Growth Hormone; D006861:Hydrogen Peroxide; D002374:Catalase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3