Mechanism of 2-methoxyestradiol-induced apoptosis and growth arrest in human breast cancer cells

✍ Scribed by Masayuki Fukui; Bao Ting Zhu

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 496 KB
• Volume: 48
• Category: Article
• ISSN: 0899-1987
• DOI: 10.1002/mc.20458

✦ Synopsis

Abstract

2‐Methoxyestradiol, a well‐known nonpolar endogenous metabolite of 17β‐estradiol, has been shown to selectively induce apoptosis in a number of cancer cell lines, but not in normal cells. The mechanism of 2‐methoxyestradiol‐induced apoptosis appears to vary considerably in different cell lines examined. In the present study, we systematically analyzed the mechanisms of 2‐methoxyestradiol‐induced apoptosis in the estrogen receptor‐negative MDA‐MB‐435s human breast cancer cells. We found that 2‐methoxyestradiol induced the activation of JNK, ERK, and p38 MAPKs. 2‐methoxyestradiol‐induced JNK activation was associated with the induction of apoptosis through the mitochondrial pathways as a result of increased phosphorylation (inactivation) of the anti‐apoptotic Bcl‐2 and Bcl‐xL proteins. In comparison, 2‐methoxyestradiol‐induced activation of ERK and p38 in these cells was found to have a protective effect against 2‐MeO‐E~2~‐induced apoptosis. Consistent with this observation, the presence of pharmacological inhibitor of ERK or p38 enhanced 2‐methoxyestradiol‐induced apoptosis. Mechanistically, inhibition of ERK and p38 activity was associated with activation of various caspases and PARP cleavage, and it also stabilized the pro‐apoptotic proteins Bax and Bim, thereby preventing them from degradation during 2‐methoxyestradiol treatment. These results suggest that ERK and p38 MAPKs may serve as viable targets for the sensitization of human breast cancer cells to 2‐methoxyestradiol‐induced apoptosis. © 2008 Wiley‐Liss, Inc.