Journal
ONCOTARGET
Volume 8, Issue 9, Pages 15364-15376Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.14970
Keywords
FM807; nasopharyngeal carcinoma; epidermal growth factor receptor; beta-catenin; Hsp90 inhibitor
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Funding
- Natural Science Foundation of Fujian Province, China [2016J01366]
- Project of International Science and Technology Cooperation of Fujian Province [2015I0002]
- Joint Funds for the Innovation of Science and Technology, Fujian province [2016Y9059]
- National Natural Science Foundation of China [81202561, 81173096]
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Nasopharyngeal carcinoma (NPC) is an epithelial malignancy usually associated with overexpression of both epidermal growth factor receptor (EGFR) and beta-catenin. FM807 is a novel curcumin analogue with antitumor activity against both poorly and well-differentiated NPC cell lines as well as good selectivity for tumor cells. FM807 actions were shown to include inhibition of cell growth, induction of necrotic/late apoptotic cell death, and G1 arrest in NPC cells. Crucially, it exhibited potent antitumor effects both in vitro and in vivo. Binding of FM807 to the N-terminus of Hsp90 disrupted Hsp90/client complexes, resulting in degradation of the Hsp90 client protein EGFR and inhibition of the downstream Raf/MEK/ERK and PI3K/AKT pathway. FM807 also depleted levels of the intranuclear transcription factors -catenin, Cyclin D1 and c-Myc levels by inhibiting Hsp90 chaperoned nuclear transport. In conjunction with its low toxicity in NPC xenograft mice, these results provide a sound preclinical basis for further development of FM807 as a novel therapeutic agent in the treatment of NPC.
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