Recent studies have shown that lycorine, a natural alkaloid compound, plays its anti-cancer role in several human malignancies including bladder cancer. However, the molecular mechanism of lycorine-induced antitumor activity has not been sufficiently investigated. The E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated protein 4 (NEDD4, also known as NEDD4-1) plays a crucial role in tumorigenesis and progression of human cancer. Therefore, depletion of NEDD4 could be a prospective therapeutic strategy for the treatment of cancer. In this study, we investigated whether lycorine restrains tumor by inhibiting the expression of NEDD4 in bladder cancer. We observed that lycorine blocked bladder cancer cell proliferation, colony formation, metastasis and invasion. Moreover, we found that overexpression of NEDD4 in bladder cancer cells significantly promoted cell proliferation and motility, whereas downregulating of the NEDD4 gene expression by lycorine or siRNA suppressed cell growth and movement. Notably, lycorine increased gemcitabine sensitivity in bladder cancer cells. Importantly, lycorine significantly reduced tumor growth, whereas overexpression of NEDD4 accelerated tumor growth and rescued lycorine-triggered tumor inhibition in xenograft mouse model. In conclusion, our study demonstrated that lycorine could exert its antineoplastic activity via suppressing NEDD4 pathway in vitro and in vivo. Therefore, inhibition of NEDD4 expression by lycorine might be a potential efficient strategy for bladder cancer.
Keywords: NEDD4; bladder cancer; gemcitabine; growth; invasion; lycorine; migration.
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