Abstract
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, has been linked to several human malignancies and shown to promote tumorigenesis. The purpose of this study was to 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 levels of proBDNF were detected in the media of A549 cells than in H1299 cell media. Using inhibitors, we found that the levels of proBDNF and mBDNF in the media are likely regulated by PI3K, AKT, and NFκB. However, the largest change in these levels resulted from MMP2/9 inhibition. Blocking p53 function in A549 cells resulted in increased mBDNF and decreased proBDNF, suggesting a role for p53 in regulating these levels. The ratio of proBDNF/mBDNF was not affected by MMP2 knockdown but increased in the media of both cell lines upon knockdown of MMP9. 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 proBDNF immunodepleted media, suggesting that MMP9 regulates the cytotoxic effects induced by proBDNF in lung cancer cells.
Highlights
Non-small-cell lung carcinoma (NSCLC) consisting of adenocarcinoma, squamous, and large-cell carcinoma accounts for ~80% of all lung cancer cases and, despite recent advances in drug development, remains highly resistant to current cancer therapeutics [1,2].Brain-derived neurotrophic factor (BDNF) (Figure 1), a member of the neurotrophin family of growth factors, and its high affinity primary receptor, tropomyosin receptor kinase B (TrkB), are widely known for the survival of neurons and synapses [3]
Higher Levels of ProBDNF Are Detected in the Media of A549 Cells than in H1299 Cell Media
We showed that immunodepletion of the neuroprotective peptide, humanin, from the media of A549 and H1299 cells increased the relative abundance of oligomer vs
Summary
Non-small-cell lung carcinoma (NSCLC) consisting of adenocarcinoma, squamous-, and large-cell carcinoma accounts for ~80% of all lung cancer cases and, despite recent advances in drug development, remains highly resistant to current cancer therapeutics [1,2].Brain-derived neurotrophic factor (BDNF) (Figure 1), a member of the neurotrophin family of growth factors, and its high affinity primary receptor, tropomyosin receptor kinase B (TrkB), are widely known for the survival of neurons and synapses [3]. Tumor cells were reported to secrete BDNF, and both BDNF and TrkB have been shown to be upregulated in a wide variety of tumors [8]. With their recognized crucial role in the progression of cancer and as part of the superfamily of growth factor receptors with tyrosine kinase activities, the Trk receptors and their signaling pathways are suggested to constitute a therapeutic target for the development of anticancer drugs [6,8]. Expression of BDNF was reported to be moderate/weak in lung cancerous tissue but not detected in normal lung tissue, while expression of TrkB was found to be moderate/weak in lung cancerous tissue and moderate in normal lung tissue [6]
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