Recombinant Analogue of the Human Protein SLURP-1 Inhibits the Growth of U251 MG and A172 Glioma Cells
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HEMISTRY, BIOPHYSICS, AND MOLECULAR BIOLOGY
Recombinant Analogue of the Human Protein SLURP-1 Inhibits the Growth of U251 MG and A172 Glioma Cells M. A. Shulepkoa, M. L. Bychkova, E. N. Lyukmanovaa,*, and Academician of the RAS M. P. Kirpichnikova,b Received March 13, 2020; revised April 16, 2020; accepted April 16, 2020
Abstract—The alpha7 nicotinic acetylcholine receptor (α7-nAChR) is considered a promising pharmacological target for the carcinoma therapy. We have previously shown that the recombinant analogue of the human protein SLURP-1 (rSLURP-1) effectively inhibits the growth of carcinomas of various origins via the interaction with α7-nAChR and down-regulation of expression of this receptor. Expression of α7-nAChR is increased in gliomas compared to healthy human brain tissues; however, the role of this receptor in the gliomas development is poorly understood. It was shown for the first time that rSLURP-1 significantly inhibits the growth of glioma model cells U251 MG and A172 up to ∼70%, which is comparable with the effect of αbungarotoxin, a selective α7-nAChR inhibitor. The half-maximum effective concentrations of rSLURP-1 for U251 MG and A172 cells were 2.82 ± 0.2 and 8.9 ± 0.3 nM, respectively. Coincubation of U251 MG cells with rSLURP-1 and the nAChR inhibitor mecamylamine attenuates the antiproliferative activity of rSLURP-1, indicating nAChR as a molecular target for the rSLURP-1 action in gliomas. Keywords: gliomas, nicotinic acetylcholine receptor, SLURP-1, Ly6/uPAR, three-loop proteins DOI: 10.1134/S1607672920040134
Gliomas are the most common primary brain tumors. Despite the use of modern treatment approaches combining surgical resection of the primary tumor tissue, radiation therapy, and chemotherapy, the average survival of patients with gliomas is only 12–15 months [1]. The low efficiency of the treatment of gliomas determines the relevance of the search for new molecular targets and the development of new drugs affecting them. One of the promising directions in the development of new anticancer drugs is the regulation of function of nicotinic acetylcholine receptors (nAChR), in particular, the subtype consisting of five identical α7 subunits (α7-nAChR) [2]. Receptors of this subtype are involved in the regulation of cancer cell proliferation, migration, and apoptosis, and the expression of the CHRNA7 gene encoding the α7 subunit of nAChR is increased in carcinoma cells [2]. In addition, the expression of the CHRNA7 gene is increased in gliomas as compared to the healthy human brain tissues [3]. However, the involvement of nAChR in the onset and development of gliomas is poorly understood. a Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry,
Russian Academy of Sciences, Moscow, Russia b Biological Faculty, Moscow State University, Moscow, Russia *e-mail: [email protected]
SLURP-1 is a secreted protein expressed in epithelium [4] and belonging to the Ly6/uPAR family of three-loop proteins [5]. Decreased expression of the SLURP-1 gene is observed in carcinomas of the colo
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