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In this study, we set out to identify regulators of intact amyloid-β40/42 (Aβ) levels in A549 (p53 wild-type) and H1299 (p53-null) lung cancer cell media. Higher Aβ levels were detected in the media of A549 than H1299 cells without or with treatment with 4-methylumbelliferone (4-MU) and/or the anti-CD44 antibody (5F12). Using inhibitors, we found that PI3K, AKT, and NFκB are likely involved in regulating Aβ levels in the media. However, increased Aβ levels that more closely resembled those found upon 4-MU co-treatment resulted from MMP2/9 inhibition, suggesting that MMP2/9 maybe the main contributors to regulation of Aβ levels in the media. Differences in Aβ levels might be accounted for, in part, by p53 since blocking p53 function in A549 cells resulted in decreased Aβ levels, increased MMP2/9 levels, increased PI3K/AKT activities and the phospho/total NFκB ratio. Using siRNA targeted against MMP2 or MMP9, we found increased Aβ levels in the media, however, MMP2 knockdown led to Aβ levels closely mimicking those detected by co-treatment with 4-MU. Cell viability or apoptosis upon treatment with either MMP2 or MMP9 siRNA along with Aβ immunodepletion, showed that MMP2 is the predominant regulator of the cytotoxic effects induced by Aβ in lung cancer cells.

Regulation of amyloid-β levels by matrix metalloproteinase-2/9 (MMP2/9) in the media of lung cancer cells