Enhancement of hypoxia-induced apoptosis of human breast cancer cells via STAT5b by momilactone B.
We have shown previously that hypoxia activates the cyclin D1 promoter via the Jak2/STAT5b pathway in breast cancer cells. Most solid tumors contain hypoxic components and overexpression of cyclin D1. The purpose of the present study was to investigate the molecular mechanism by which momilactone B exerts its inhibitory effects on breast cancer cells. Momilactone B, extracted from Korean rice hulls, suppressed hypoxia-induced increases in phospho-STAT5, STAT5b, cyclin D1, and cdk4 protein levels in human breast cancer cells. STAT5b expression was inhibited by siRNA experiments leading to decreased cyclin D1. The effects of momilactone B on cell growth and apoptosis-related gene expression were investigated in breast cancer cells under hypoxic conditions (2% O2). Bax and p21 expression was found to be up-regulated, whereas ppRb and bcl-2 were down-regulated in momilactone B-treated cells under hypoxic conditions. However, the p53 protein level did not change. Flow cytometry with Annexin-FITC staining showed that the number of apoptotic cells increased in hypoxic cells treated with momilactone B compared with untreated hypoxic cells. Furthermore, caspase activity increased upon treatment with momilactone B under hypoxic conditions. These results indicate that momilactone B inhibits the growth of breast cancer cells, regulates the expression of apoptosis-related genes, and induces apoptosis through STAT5b and a caspase-3 dependent pathway. We suggest that momilactone B accelerates hypoxia-induced apoptosis of human breast cancer cells through STAT5b, and may represent an effective chemopreventive or therapeutic agent against breast cancer.
Joung
Youn-Hee
YH
Department of Pathology, School of Medicine, and Bio-Food and Drug Research Center, Konkuk University, Chungju City 380-701, Korea.
Lim
Eun-Joung
EJ
Kim
Mi-Sun
MS
Lim
So Dug
SD
Yoon
So-Young
SY
Lim
Young Chang
YC
Yoo
Young Bum
YB
Ye
Sang-Kyu
SK
Park
Taekyu
T
Chung
Ill-Min
IM
Bae
Ki-Yeol
KY
Yang
Young Mok
YM
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000187:drug effects / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000187:drug effects / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor / Q000187:drug effects* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004224:Diterpenes; D007783:Lactones; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D051028:bcl-2-Associated X Protein; C477203:momilactone B; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4