Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, has been linked to various steps involved in carcinogenesis and shown to promote tumorigenesis. Here, we explore the relative abundance of pro-brain-derived neurotrophic factor (proBDNF) and mature BDNF (mBDNF) in A549 (p53 wild-type) and H1299 (p53-null) lung cancer cell media. Higher proBDNF levels were detected in the media of A549 cells than in H1299 cell media. Using inhibitors, we show that the levels of proBDNF and mBDNF in the media are likely regulated by PI3K, AKT, and NFκB. However, MMP2/9 inhibition resulted in the largest change in these levels. Blocking p53 function in A549 cells led to increased mBDNF and decreased proBDNF, suggesting a role for p53 in regulating these levels. The ratio of proBDNF/mBDNF increased in the media of both cell lines upon knockdown of MMP9 but was not affected by MMP2 knockdown. Downregulation of either MMP2 or MMP9 by siRNA showed that MMP9 siRNA treatment of either A549 or H1299 cells resulted in decreased cell viability and increased apoptosis, an effect diminished upon the same treatment with media immunodepleted of proBDNF, suggesting that MMP9 plays a role in regulating the cytotoxic effects induced by proBDNF in lung cancer cells.
Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R15GM131222 to H.G.E.
