Toxin from black mamba venom inhibits growth of glioma cells selectively expressing ASIC1a channels
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.
The researchers from the Laboratory of Bioengineering of Neuromodulators and Neuroreceptors, the Laboratory of Structural Biology of Ion Channels, the Laboratory of Neuroreceptors and Neuroregulators, and the Laboratory of membrane bioenergetics of the Institute of Bioorganic Chemistry, Russian Academy of Sciences, together with the researchers from the Institute of Cytology of the Russian Academy of Sciences, demonstrated for the first time the expression of functionally active ASIC1a channels in U251 MG and A172 gliomas cells, but not in normal astrocytes. A recombinant analogue of mambalgin-2 from black mamba venom was used to suppress the cation influx through ASIC1a channels in glioma cells. As it turned out, mambalgin-2 inhibits the growth of U251 MG and A172 gliomas with EC 50 in the nanomolar range, while not affecting the proliferation of normal astrocytes. Notably, mutant variants of mambalgin-2 with impaired affinity for ASIC1a did not affect the proliferation of glioma cells. Thus, it was confirmed that these channels are the main molecular target of mambalgin-2 in glioma cells. It was shown that the decrease in the growth of MG U251 and A172 gliomas cells using mambalgin-2 is associated with the cell cycle arrest, inhibition of phosphorylation of cyclin D1 and cyclin-dependent kinases (CDK), and apoptosis induction. The antiproliferative activity of mambalgin-2 and the prospect of its use as a prototype for the development of new drugs for the treatment of gliomas was confirmed on primary cells obtained from a patient with glioblastoma. Thus, a new antiproliferative activity of mambalgin-2 was identified and characterized, which can become the basis for therapy for other cancers expressing ASIC1a.
This work was supported by the Russian Foundation for Basic Research (projects "Study of the molecular mechanisms underlying the antitumor activity of the three-finger toxin mambalgin-2", supervisor M.L. Bychkov and "New approaches for targeted therapy of gliomas based on tumor profiling by biochemical markers, biophysical properties of cells and metabolic activity ", supervisor Prof. Z.O. Shenkarev) and published in Cancers.