Regulation of the Soluble Amyloid Precursor Protein α (sAPPα) Levels by Acetylcholinesterase and Brain-Derived Neurotrophic Factor in Lung Cancer Cell Media

Khashali, Hind Al; Ray, Ravel; Coleman, Kai-ling; Atali, Sarah; Haddad, Ben; Wareham, Jadziah; Guthrie, Jeffrey; Heyl, Deborah L.; Evans, Hedeel Guy

doi:10.3390/ijms231810746

Cited by 10 publications

(50 citation statements)

References 92 publications

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“…As previously reported [ 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ], 25 cm 2 tissue culture flasks were seeded with either human A549 (ATCC CCL-185) or H1299 (ATCC CRL-5803) NSCLC cells (ATCC, Manassas, VA, USA) in 5 mL of HyClone DMEM/F12 medium (GE Healthcare Life Sciences, Pittsburgh, PA, USA) supplemented with 10% Fetalgro BGS (RMBIO, Missoula, MT, USA) and 50 U/mL penicillin-streptomycin (Invitrogen Life Technologies, Carlsbad, CA, USA). Cells were grown overnight in an incubator set to 37 °C, 95% humidity, and 5% CO 2 .…”

Section: Methodssupporting

confidence: 75%

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Opposing Roles of IGFBP-3 and Heparanase in Regulating A549 Lung Cancer Cell Survival

Khashali

Wareham

Ray

et al. 2022

Cells

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In this study, we examined the roles of heparanase and IGFBP-3 in regulating A549 and H1299 non-small-cell lung cancer (NSCLC) survival. We found that H1299 cells, known to be p53-null with no expression of IGFBP-3, had higher heparanase levels and activity and higher levels of heparan sulfate (HS) in the media compared to the media of A549 cells. Inhibiting heparanase activity or its expression using siRNA had no effect on the levels of IGFBP-3 in the media of A549 cells, reduced the levels of soluble HS fragments, and led to decreased interactions between IGFBP-3 and HS in the media. HS competed with HA for binding to IGFBP-3 or IGFBP-3 peptide (215-KKGFYKKKQCRPSKGRKR-232) but not the mutant peptide (K228AR230A). HS abolished the cytotoxic effects of IGFBP-3 but not upon blocking HA-CD44 signaling with the anti-CD44 antibody (5F12). Blocking HA-CD44 signaling decreased the levels of heparanase in the media of both A549 and H1299 cell lines and increased p53 activity and the levels of IGFBP-3 in A549 cell media. Knockdown of p53 led to increased heparanase levels and reduced IGFBP-3 levels in A549 cell media while knockdown of IGFBP-3 in A549 cells blocked p53 activity and increased heparanase levels in the media.

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Section: Methodssupporting

confidence: 75%

“…ELISAs were conducted, as we reported previously, using Nunc MaxiSorp 96-well Flat-Bottom plate (ThermoFisher) wells [ 50 , 51 , 54 , 57 , 60 ]. All absorbance measurements were in the linear range.…”

Section: Methodsmentioning

confidence: 99%

Opposing Roles of IGFBP-3 and Heparanase in Regulating A549 Lung Cancer Cell Survival

Khashali

Wareham

Ray

et al. 2022

Cells

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“…Treatment with BDNF attenuated cisplatin-induced cell death and decreased the chemosensitivity of neuroblastoma cells to cisplatin, an effect that was blocked by cell treatment with the PI3K inhibitor, LY294002, suggesting a role of PI3K in BDNF’s rescue effects [ 41 ]. Our laboratory recently showed that treatment with acetylcholinesterase, well-known for its classical role in the catalytic hydrolysis of cholinergic neurotransmitters, shifted processing of the amyloid precursor protein away from the non-amyloidogenic pathway and toward the amyloidogenic pathway, whereas treatment with BDNF led to opposite effects [ 42 ]. While nicotine was earlier reported to regulate changes in the levels of BDNF that can affect nAChRs, and vice versa, in the brain from animal studies, relatively little is known about the interplay between nicotine and BDNF in NSCLC [ 38 , 39 , 43 , 44 ].…”

Section: Introductionmentioning

confidence: 99%

Regulation of Cisplatin Resistance in Lung Cancer Cells by Nicotine, BDNF, and a β-Adrenergic Receptor Blocker

Ray

Khashali

Haddad

et al. 2022

IJMS

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It is well-recognized that cigarette smoking is a primary risk factor in the development of non-small cell lung cancer (NSCLC), known to account for ~80% of all lung cancers with nicotine recognized as the major addictive component. In investigating the effect of nicotine, brain-derived neurotrophic factor (BDNF), and the β-adrenergic receptor blocker, propranolol, on sensitivity of NSCLC cell lines, A549 and H1299, to cisplatin, we found increased cell viability, and enhanced cisplatin resistance with nicotine and/or BDNF treatment while opposite effects were found upon treatment with propranolol. Cell treatment with epinephrine or nicotine led to EGFR and IGF-1R activation, effects opposite to those found with propranolol. Blocking EGFR and IGF-1R activation increased cell sensitivity to cisplatin in both cell lines. PI3K and AKT activities were upregulated by nicotine or BDNF and downregulated by cell treatment with inhibitors against EGFR and IGF-1R and by propranolol. Apoptosis and cell sensitivity to cisplatin increased upon co-treatment of cells with cisplatin and inhibitors against PI3K or AKT. Our findings shed light on an interplay between nicotine, BDNF, and β-Adrenergic receptor signaling in regulating survival of lung cancer cells and chemoresistance which can likely expand therapeutic opportunities that target this regulatory network in the future.

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“…We also reported minimal levels of AChE in H1299 cell media as compared to the media of A549 cells 36 and higher levels of mature brain-derived neurotrophic factor in the media of H1299 cells than in A549 cell media 37 . More recently, we showed that sAPPα levels are regulated by AChE and mBDNF and are higher in the media of H1299 cells compared to A549 cell media 38 .…”

Section: Introductionmentioning

confidence: 94%

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

Haddad,

Khalil,

Al Khashali

et al. 2024

Sci Rep

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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.

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Regulation of the Soluble Amyloid Precursor Protein α (sAPPα) Levels by Acetylcholinesterase and Brain-Derived Neurotrophic Factor in Lung Cancer Cell Media

Cited by 10 publications

References 92 publications

Opposing Roles of IGFBP-3 and Heparanase in Regulating A549 Lung Cancer Cell Survival

Opposing Roles of IGFBP-3 and Heparanase in Regulating A549 Lung Cancer Cell Survival

Regulation of Cisplatin Resistance in Lung Cancer Cells by Nicotine, BDNF, and a β-Adrenergic Receptor Blocker

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

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