The role of leptin in regulation of the soluble amyloid precursor protein α (sAPPα) levels in lung cancer cell media
Abstract Previously, we found that the levels of soluble amyloid precursor protein α (sAPPα) 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 sAPPα levels in the media by leptin, a widely...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-55717-y |
| _version_ | 1797274737192206336 |
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| author | Ben Haddad Jeneen Khalil Hind Al Khashali Ravel Ray Stuti Goel Ban Darweesh Kai-ling Coleman Caroline Wozniak Robert Ranzenberger Brooke Lopo Jeffrey Guthrie Deborah Heyl Hedeel Guy Evans |
| author_facet | Ben Haddad Jeneen Khalil Hind Al Khashali Ravel Ray Stuti Goel Ban Darweesh Kai-ling Coleman Caroline Wozniak Robert Ranzenberger Brooke Lopo Jeffrey Guthrie Deborah Heyl Hedeel Guy Evans |
| author_sort | Ben Haddad |
| collection | DOAJ |
| description | Abstract Previously, we found that the levels of soluble amyloid precursor protein α (sAPPα) 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 sAPPα 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 sAPPα, that were accompanied by lower Aβ40/42 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 sAPPα and increased levels of Aβ40/42 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 sAPPα, 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 sAPPα levels in the media, and highlights the importance of targeting leptin as a potential therapeutic strategy for NSCLC treatment. |
| first_indexed | 2024-03-07T15:02:32Z |
| format | Article |
| id | doaj.art-a2476713c7254f3ca4829719b4de6d2f |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-07T15:02:32Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-a2476713c7254f3ca4829719b4de6d2f2024-03-05T19:03:15ZengNature PortfolioScientific Reports2045-23222024-02-0114111610.1038/s41598-024-55717-yThe role of leptin in regulation of the soluble amyloid precursor protein α (sAPPα) levels in lung cancer cell mediaBen Haddad0Jeneen Khalil1Hind Al Khashali2Ravel Ray3Stuti Goel4Ban Darweesh5Kai-ling Coleman6Caroline Wozniak7Robert Ranzenberger8Brooke Lopo9Jeffrey Guthrie10Deborah Heyl11Hedeel Guy Evans12Chemistry Department, Eastern Michigan UniversityChemistry Department, Eastern Michigan UniversityChemistry Department, Eastern Michigan UniversityChemistry Department, Eastern Michigan UniversityChemistry Department, Eastern Michigan UniversityChemistry Department, Eastern Michigan UniversityChemistry Department, Eastern Michigan UniversityChemistry Department, Eastern Michigan UniversityChemistry Department, Eastern Michigan UniversityChemistry Department, Eastern Michigan UniversityChemistry Department, Eastern Michigan UniversityChemistry Department, Eastern Michigan UniversityChemistry Department, Eastern Michigan UniversityAbstract Previously, we found that the levels of soluble amyloid precursor protein α (sAPPα) 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 sAPPα 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 sAPPα, that were accompanied by lower Aβ40/42 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 sAPPα and increased levels of Aβ40/42 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 sAPPα, 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 sAPPα levels in the media, and highlights the importance of targeting leptin as a potential therapeutic strategy for NSCLC treatment.https://doi.org/10.1038/s41598-024-55717-y |
| spellingShingle | Ben Haddad Jeneen Khalil Hind Al Khashali Ravel Ray Stuti Goel Ban Darweesh Kai-ling Coleman Caroline Wozniak Robert Ranzenberger Brooke Lopo Jeffrey Guthrie Deborah Heyl Hedeel Guy Evans The role of leptin in regulation of the soluble amyloid precursor protein α (sAPPα) levels in lung cancer cell media Scientific Reports |
| title | The role of leptin in regulation of the soluble amyloid precursor protein α (sAPPα) levels in lung cancer cell media |
| title_full | The role of leptin in regulation of the soluble amyloid precursor protein α (sAPPα) levels in lung cancer cell media |
| title_fullStr | The role of leptin in regulation of the soluble amyloid precursor protein α (sAPPα) levels in lung cancer cell media |
| title_full_unstemmed | The role of leptin in regulation of the soluble amyloid precursor protein α (sAPPα) levels in lung cancer cell media |
| title_short | The role of leptin in regulation of the soluble amyloid precursor protein α (sAPPα) levels in lung cancer cell media |
| title_sort | role of leptin in regulation of the soluble amyloid precursor protein α sappα levels in lung cancer cell media |
| url | https://doi.org/10.1038/s41598-024-55717-y |
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