The role of leptin in regulation of the soluble amyloid precursor protein (sAPP) levels in lung cancer cell media

Previously, we found that the levels of soluble amyloid precursor protein alpha (sAPP alpha) are regulated, in part, by acetylcholinesterase (AChE) in human A549 (p53 wild-type) and H1299 (p53-null) NSCLC cell lines. In this study, we found regulation of sAPP alpha levels in the media by leptin, a widely recognized obesity-associated adipokine that has recently been shown to play a possible role in cancer signaling. Increased levels of sAPP alpha, that were accompanied by lower A beta 40/42 levels in the media of A549 and H1299 cells, were detected upon cell incubation with leptin. Conversely, knockdown of leptin or its receptor led to reduced levels of sAPP alpha and increased levels of A beta 40/42 in the media of A549 and H1299 cells, suggesting that leptin likely shifts APP processing toward the non-amyloidogenic pathway. A549 cell treatment with leptin increased acetylcholine levels and blocked the activities of AChE and p53. Treatment with leptin resulted in increased activation of PKC, ERK1/2, PI3K, and the levels of sAPP alpha, effects that were reversed by treatment with kinase inhibitors and/or upon addition of AChE to A549 and H1299 cell media. Cell viability increased by treatment of A549 and H1299 cells with leptin and decreased upon co-treatment with AChE and/or inhibitors targeting PKC, ERK1/2, and PI3K. This study is significant as it provides evidence for a likely carcinogenic role of leptin in NSCLC cells via upregulation of sAPP alpha levels in the media, and highlights the importance of targeting leptin as a potential therapeutic strategy for NSCLC treatment.