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Article

Mambalgin-2 Induces Cell Cycle Arrest and Apoptosis in Glioma Cells via Interaction with ASIC1a

1
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 119997 Moscow, Russia
2
Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia
3
Institute of Cytology, Russian Academy of Science, 194064 St-Petersburg, Russia
4
Federal State Autonomous Institution, N.N. Burdenko National Medical Research Center of Neurosurgery, 125047 Moscow, Russia
5
Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
6
Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology (State University), 141701 Dolgoprudny, Moscow Region, Russia
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(7), 1837; https://doi.org/10.3390/cancers12071837
Received: 19 May 2020 / Revised: 27 June 2020 / Accepted: 2 July 2020 / Published: 8 July 2020
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
Gliomas are fast growing and highly invasive brain tumors, characterized by tumor microenvironment acidification that drives glioma cell growth and migration. Channels containing Acid-sensing Ion Channel 1a subunit (ASIC1a) mediate amiloride-sensitive cation influx in late stage glioma cells, but not in normal astrocytes. Thus, selective targeting of ASIC1a can be a perspective strategy for glioma treatment. Here, ASIC1a expression in U251 MG and A172 glioma cells, but not in normal astrocytes, was demonstrated. Recombinant analog of mambalgin-2 from black mamba Dendroaspis polylepis inhibited amiloride-sensitive currents at ASIC1a both in Xenopus laevis oocytes and in U251 MG cells, while its mutants with impaired activity towards this channel did not. Mambalgin-2 inhibited U251 MG and A172 glioma cells growth with EC50 in the nanomolar range without affecting the proliferation of normal astrocytes. Notably, mambalgin-2 mutants did not affect glioma cell proliferation, pointing on ASIC1a as the main molecular target of mambalgin-2 in U251 MG and A172 cells. Mambalgin-2 induced a cell cycle arrest, inhibited Cyclin D1 and cyclin-dependent kinases (CDK) phosphorylation and caused apoptosis in U251 MG and A172 cells. Moreover, mambalgin-2 inhibited the growth of low-passage primary cells from a patient with glioblastoma. Altogether, our data point to mambalgin-2 as a useful hit for the development of new drugs for glioma treatment. View Full-Text
Keywords: glioblastoma; astrocytes; mambalgin-2; amiloride-sensitive ion channels; ASIC; cell cycle; apoptosis; Ly6/uPAR; three-finger proteins glioblastoma; astrocytes; mambalgin-2; amiloride-sensitive ion channels; ASIC; cell cycle; apoptosis; Ly6/uPAR; three-finger proteins
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MDPI and ACS Style

Bychkov, M.; Shulepko, M.; Osmakov, D.; Andreev, Y.; Sudarikova, A.; Vasileva, V.; Pavlyukov, M.S.; Latyshev, Y.A.; Potapov, A.A.; Kirpichnikov, M.; Shenkarev, Z.O.; Lyukmanova, E. Mambalgin-2 Induces Cell Cycle Arrest and Apoptosis in Glioma Cells via Interaction with ASIC1a. Cancers 2020, 12, 1837. https://doi.org/10.3390/cancers12071837

AMA Style

Bychkov M, Shulepko M, Osmakov D, Andreev Y, Sudarikova A, Vasileva V, Pavlyukov MS, Latyshev YA, Potapov AA, Kirpichnikov M, Shenkarev ZO, Lyukmanova E. Mambalgin-2 Induces Cell Cycle Arrest and Apoptosis in Glioma Cells via Interaction with ASIC1a. Cancers. 2020; 12(7):1837. https://doi.org/10.3390/cancers12071837

Chicago/Turabian Style

Bychkov, Maxim, Mikhail Shulepko, Dmitry Osmakov, Yaroslav Andreev, Anastasia Sudarikova, Valeria Vasileva, Marat S. Pavlyukov, Yaroslav A. Latyshev, Alexander A. Potapov, Mikhail Kirpichnikov, Zakhar O. Shenkarev, and Ekaterina Lyukmanova. 2020. "Mambalgin-2 Induces Cell Cycle Arrest and Apoptosis in Glioma Cells via Interaction with ASIC1a" Cancers 12, no. 7: 1837. https://doi.org/10.3390/cancers12071837

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