IGF-I plus E2 induces proliferation via activation of ROS-dependent ERKs and JNKs in human breast carcinoma cells
✍ Scribed by Cheng-Wei Lin; Liang-Yo Yang; Shing-Chuan Shen; Yen-Chou Chen
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 507 KB
- Volume
- 212
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Induction of 17β‐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. J. Cell. Physiol. 212:666–674, 2007. © 2007 Wiley‐Liss, Inc.