Abstract
Lynx1 is the first three-finger prototoxin found in the mammalian central nervous system. It is a GPI-anchored protein modulating nicotinic acetylcholine receptors (nAChRs) in the brain. Besides the brain, the Lynx1 protein was found in the lung and kidney. Endogenous Lynx1 controls the nicotine-induced up-regulation of the expression of α7 type nAChRs in lung adenocarcinoma A549 cells as well as the cell growth. Here, we analyzed the Lynx1 expression in the set of human epithelial cells. The Lynx1 expression both at the mRNA and protein level was detected in normal oral keratinocytes, and lung, colon, epidermal, and breast cancer cells, but not in embryonic kidney cells. Co-localization of Lynx1 with α7-nAChRs was revealed in a cell membrane for lung adenocarcinoma A549 and colon carcinoma HT-29 cells, but not for breast adenocarcinoma MCF-7 and epidermoid carcinoma A431 cells. The recombinant water-soluble variant of Lynx1 without a GPI-anchor (ws-Lynx1) inhibited the growth of A549 cells causing cell cycle arrest via modulation of α7-nAChRs and activation of different intracellular signaling cascades, including PKC/IP3, MAP/ERK, p38, and JNK pathways. A549 cells treatment with ws-Lynx1 resulted in phosphorylation of the proapoptotic tumor suppressor protein p53 and different kinases participated in the regulation of gene transcription, cell growth, adhesion, and differentiation. Externalization of phosphatidylserine, an early apoptosis marker, observed by flow cytometry, confirmed the induction of apoptosis in A549 cells upon the ws-Lynx1 treatment. Our data revealed the ability of ws-Lynx1 to regulate homeostasis of epithelial cancer cells.
Highlights
Colorectal carcinoma HT-29 cells were demonstrated the expression of the α4, α5, α7, and β1 genes [39], while we found the expression of the α9 Nicotinic acetylcholine receptors (nAChRs) subunit
It was previously shown that epidermoid carcinoma A431 cells express the α7 nAChR gene [40], and the expression of the α3 gene was reported in the Human Protein Atlas (HPA) database, while we detected the expression of the α4, α9, and β2 genes
We found that the water-soluble variant of human Lynx1 controls the growth and apoptosis of non-small lung cancer cells
Summary
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels responsible for signal transduction in the central and peripheral nervous systems and in the neuromuscular. The expression of different nAChR subunits was described in epithelial human cancers, e.g. in lung cancer, mesothelioma and colon carcinoma [6]. LYNX1 expression was found in normal human epidermal keratinocytes [27] These data indicate that Lynx could be expressed in the nervous system, and could participate in the regulation of epithelial cell homeostasis. We studied the Lynx expression in human cells of epithelial origin (normal oral keratinocytes Het-1A, embryonic kidney cells HEK-293T, epidermoid carcinoma A431, breast adenocarcinoma MCF-7, lung adenocarcinoma A549 and colon carcinoma HT-29). Data obtained revealed the ability of ws-Lynx to regulate homeostasis of cancer cells via interaction with α7-nAChRs, causing the cell cycle arrest and activation of proapoptotic intracellular cascades
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