IGF-I plus E2 induces proliferation via activation of ROS-dependent ERKs and JNKs in human breast carcinoma cells.
Induction of 17beta-estradiol (E2) and insulin-like growth factor-I (IGF-I) has been detected in breast carcinoma, however the interaction between E2 and IGF-I in the proliferation of breast carcinoma cells is still unclear. In the present study, we found that IGF-I enhances the E2-induced proliferation in MCF-7 human breast carcinoma cells in accordance with stimulation of colony formation via a soft agar assay. Activation of insulin receptor substrate-1 (IRS-1) protein and extracellular signal-related kinases (ERKs) and c-Jun N-terminal kinases (JNKs), but not p38 mitogen-activated protein kinase (MAPK), via phosphorylation induction was detected in MCF-7 cells treated with IGF-I plus E2 (E2/IGF-I). E2/IGF-I-induced proliferation was blocked by chemical inhibitors of ERKs (PD98059) and JNKs (SP600125). An increase in the expression of c-Jun protein was detected in E2/IGF-I-treated MCF-7 cells, and this was inhibited by PD98059 and SP600125. Transfection of the dominant negative MEKK and JNK plasmids significantly reduced E2/IGF-I-induced proliferation with suppression of c-Jun protein expression. An increase in peroxide production was detected in E2/IGF-I-treated cells, and N-acetyl-L-cysteine (NAC) and Tiron (TIR) addition significantly inhibited E2/IGF-I-induced cell proliferation with blocking of the phosphorylation of ERKs and JNKs, and the expression of c-Jun protein. Additionally, 3-OH flavone, baicalein, and quercetin showed effective inhibitory activities against E2/IGF-I-induced proliferation through suppressing proliferative events such as phosphorylation of IRS-1, ERKs, and JNKs proteins, and induction of c-Jun protein and colony formation. These results indicate that IGF-I interacts with E2 to promote the proliferation of breast carcinoma cells via ROS-dependent MAPK activation and c-Jun protein expression. The structure-related inhibition of E2/IGF-I-induced proliferative events by flavonoids is elucidated.
Lin
Cheng-Wei
CW
Graduate Institute of Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
Yang
Liang-Yo
LY
Shen
Shing-Chuan
SC
Chen
Yen-Chou
YC
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000873:Anthracenes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004958:Estradiol / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D044950:Flavanones / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006027:Glycosides / Q000494:pharmacology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014162:Transfection
D000873:Anthracenes; D000970:Antineoplastic Agents; D000975:Antioxidants; D044950:Flavanones; D005419:Flavonoids; D006027:Glycosides; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; C432165:pyrazolanthrone; C006680:baicalein; D004958:Estradiol; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D007334:Insulin-Like Growth Factor I; D011794:Quercetin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000111:Acetylcysteine; C041477:3-hydroxyflavone