期刊
ONCOTARGET
卷 7, 期 22, 页码 32566-32578出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.8873
关键词
Inulanolide A; NFAT1-MDM2 pathway; p53-independent; breast cancer orthotopic tumor model; metastasis
资金
- American Cancer Society (ACS) [RSG-15-009-01-CDD]
- National Institutes of Health (NIH) [R01 CA186662, CA102514]
The transcription factor NFAT1 and the oncogene MDM2 have crucial roles in breast cancer development, progression, and metastasis. We have recently discovered that NFAT1 activates MDM2 expression. Here, we identified a small molecule (named Inulanolide A) that dually inhibited both NFAT1 and MDM2 in breast cancer cells in vitro and in vivo. Unlike conventional MDM2 inhibitors, Inulanolide A (InuA) exerted its selective anticancer activity in both p53-dependent and -independent manners. InuA decreased cell proliferation and induced G2/M phase arrest and apoptosis in breast cancer cells; it also led to a decrease in MDM2, NFAT1 and proteins associated with cell proliferation, and an increase in apoptotic signal related proteins. In a mouse orthotopic model, JapA suppressed tumor growth and lung metastasis without host toxicity. Thus, InuA is a novel NFAT1 and MDM2 dual targeting agent and may be a clinical candidate for breast cancer therapy. This study also validates the effectiveness of dually targeting NFAT1 and MDM2 in breast cancer.
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