The molecular mechanism of dehydrocostuslactone in human breast cancer cell lines
| Autor: | Wen-Chiu Ni, 倪雯秋 |
|---|---|
| Rok vydání: | 2008 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 96 This study is the first to investigate the anticancer effect of DHE in human breast cancer cells. DHE exhibited cell proliferation inhibition by inducing cells to undergo G2/M arrest and apoptotic death. DHE treatment blocked the progression of cell cycle at G0/G1-S phase in MCF-7, but at S-G2/M phase in MDA-MB-231 cells. Blockade of the cell cycle at G0/G1-S in MCF-7 was associated with increased p53 and p21, and reduced amounts of cyclin D1, cyclin D2, cdk2 and cdk 4. In contrast, DHE caused S-G2/M phase arrest by decreasing the expression of cyclin A and cyclin B, and increasing the levels of inactivated phospho-Cdc2 and phospho-Cdc25C by Chk1 activation. DHE induced apoptosis through caspases-independent pathway. Pretreatment of cells with pan-caspase inhibitor failed to affect DHE-mediated cell death. In addition, DHE increased the translocation of apoptosis inducing factor (AIF) and endonuclease G (Endo G) from mitochondria to nuclei, resulting in DNA fragmentation. We also found that DHE inhibited survival signaling through the janus tyrosine kinases (JAK)/signal transducers and activators of transcription 3 (STAT3) signaling pathway by blocking the phosphorylation of JAK and its downstream targets STAT3. Furthermore, nuclei translocation and DNA binding activity of STAT3 were also inhibited by DHE treatment in both cancer cell lines. Blockade of the activation of JAK/STAT3 was associated with increased suppressor of cytokine signaling-1 and -3 (SOCS-1 and -3) expression. Taken together, these results imply a critical role for JAK/STAT3 inhibition in DHE-induced cell cycle arrest and apoptosis of human breast cancer cells. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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