SOCS1 induced by NDRG2 expression negatively regulates STAT3 activation in breast cancer cells.
Although NDRG2 inactivation has recently been found to have an important role in some tumorigenesis, its role in intracellular signal transduction pathways remains poorly defined. In the present study, we demonstrate that NDRG2 overexpression in malignant breast cancer cells specifically inhibits Akt phosphorylation and induces phosphorylation of p38 MAP kinase and SAPK/JNK. In addition, we investigated whether NDRG2 expression affects JAK/STAT- or mitogen-activated protein kinase-mediated signal activation. JAK2 or STAT3 activation in both resting and IGF-stimulating cells was remarkably inhibited by NDRG2 expression. Furthermore, NDRG2 has been found to highly up-regulate the expression level of SOCS1 mRNA and protein. We have found that NDRG2 was able to regulate cytokine signaling in breast cancer cells through the regulation of SOCS1 expression. Finally, inhibition of p38 MAPK activity blocked the induction of SOCS1 expression by NDRG2, resulting in the recovery of STAT3 phosphorylation level. Together, these data demonstrate that NDRG2 expression in breast cancer cells is able to inhibit STAT3 activation via SOCS1 induction in a p38 MAPK dependent manner, implicating NDRG2 as a growth inhibitory gene in signal transduction pathways of breast tumor cells.
Park
Yongjin
Y
Department of Biological Sciences and the Research Center for Women's Diseases, Sookmyung Women's University, Chungpa-Dong, Yongsan-Gu, Seoul 140-742, Republic of Korea.
Shon
Soo-Kyung
SK
Kim
Aeyung
A
Kim
Keun Il
KI
Yang
Young
Y
Cho
Dae Ho
DH
Lee
Myeong-Sok
MS
Lim
Jong-Seok
JS
D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C466228:NDRG2 protein, human; C108944:SOCS1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D025521:Tumor Suppressor Proteins; D048051:p38 Mitogen-Activated Protein Kinases