Mambalgin-2 Inhibits Growth, Migration, and Invasion of Metastatic Melanoma Cells by Targeting the Channels Containing an ASIC1a Subunit Whose Up-Regulation Correlates with Poor Survival Prognosis

Bychkov, Maxim L.; Kirichenko, Artem V.; Shulepko, Mikhail A.; Mikhaylova, I. N.; Kirpichnikov, Mikhaǐl P.; Lyukmanova, Ekaterina N.

doi:10.3390/biomedicines9101324

Cited by 13 publications

(19 citation statements)

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“…Melanoma growth is accompanied by acidification of the tumor microenvironment to pH ~6.5 instead of ~7.4 in normal conditions [30]. Acidification of the microenvironment is a significant factor that promotes tumor progression [31] and determines the properties of melanoma EVs [32]. EVs can stimulate migration and invasion of metastatic non-invasive melanoma cells [32]; however, the EVs' influence on keratinocytes homeostasis was not studied yet.…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles Derived from Acidified Metastatic Melanoma Cells Stimulate Growth, Migration, and Stemness of Normal Keratinocytes

et al. 2022

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Metastatic melanoma is a highly malignant tumor. Melanoma cells release extracellular vesicles (EVs), which contribute to the growth, metastasis, and malignancy of neighboring cells by transfer of tumor-promoting miRNAs, mRNA, and proteins. Melanoma microenvironment acidification promotes tumor progression and determines EVs’ properties. We studied the influence of EVs derived from metastatic melanoma cells cultivated at acidic (6.5) and normal (7.4) pH on the morphology and homeostasis of normal keratinocytes. Acidification of metastatic melanoma environment made EVs more prooncogenic with increased expression of prooncogenic mi221 RNA, stemless factor CD133, and pro-migration factor SNAI1, as well as with downregulated antitumor mir7 RNA. Incubation with EVs stimulated growth and migration both of metastatic melanoma cells and keratinocytes and changed the morphology of keratinocytes to stem-like phenotype, which was confirmed by increased expression of the stemness factors KLF and CD133. Activation of the AKT/mTOR and ERK signaling pathways and increased expression of epidermal growth factor receptor EGFR and SNAI1 were detected in keratinocytes upon incubation with EVs. Moreover, EVs reduced the production of different cytokines (IL6, IL10, and IL12) and adhesion factors (sICAM-1, sICAM-3, sPecam-1, and sCD40L) usually secreted by keratinocytes to control melanoma progression. Bioinformatic analysis revealed the correlation between decreased expression of these secreted factors and worse survival prognosis for patients with metastatic melanoma. Altogether, our data mean that metastatic melanoma EVs are important players in the transformation of normal keratinocytes.

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Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles Derived from Acidified Metastatic Melanoma Cells Stimulate Growth, Migration, and Stemness of Normal Keratinocytes

et al. 2022

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“…In addition to a high level of ASIC expression in the nervous system, where they are involved in physiological processes such as pain perception, synaptic plasticity, learning, and memory, most ASIC and ENaC subunits are present in different non-excitable tissues, and the channels formed by them can also be implicated in tumor pathogenesis. Our previous results and literature data point on the possible ASIC1 and ENaC expressions in leukemia ( 15 ), glioma ( 16 ), melanoma ( 17 ), breast cancer ( 18 ), and pancreatic ( 19 ), lung ( 3 ), and hepatocellular carcinoma cells ( 20 ), where the ASIC1-containing channels participate in the regulation of cancer cell proliferation, migration, and invasion. In particular, the ASIC1a-containing channels affect the proliferation and migration of lung adenocarcinoma A549 cells induced by extracellular acidosis ( 3 ).…”

Section: Introductionmentioning

confidence: 79%

“…Previously, we showed that the recombinant analogue of mambalgin-2 inhibits the growth of leukemia ( 15 ) and glioma cells ( 16 ) and the growth and migration of melanoma cells ( 17 ). Here, we tested mambalgin-2’s effect on lung adenocarcinoma A549 and Lewis cells, lung transformed WI-38 fibroblasts, and lung normal HLF fibroblasts.…”

Section: Resultsmentioning

confidence: 99%

“…Here, we tested mambalgin-2’s effect on lung adenocarcinoma A549 and Lewis cells, lung transformed WI-38 fibroblasts, and lung normal HLF fibroblasts. As the acidification of the cell media results in stimulation of the growth, migration, and invasion of melanoma cells and influences the expression pattern of the ASIC and ENac subunits ( 17 ), we studied mambalgin-2’s activity in cells cultivated in the normal (pH 7.4) and acidic (pH 5.5) media.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we have proposed that the target of mambalgin-2 in melanoma cells could be the heteromeric acid-sensitive channels ASIC1/α-ENaC/γ-ENaC ( 17 ). To investigate whether mambalgin-2 interacts with the ASIC1a, α-ENaC, and γ-ENaC subunits in A549 cells, we performed an extraction of these subunits from the membrane fraction of A549 cells by affinity chromatography using an N-hydroxysuccinimide resin coupled with mambalgin-2.…”

Section: Resultsmentioning

confidence: 99%

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Mambalgin-2 Inhibits Lung Adenocarcinoma Growth and Migration by Selective Interaction With ASIC1/α-ENaC/γ-ENaC Heterotrimer

Sudarikova

Bychkov²,

Kulbatskii³

et al. 2022

Front. Oncol.

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Lung cancer is one of the most common cancer types in the world. Despite existing treatment strategies, overall patient survival remains low and new targeted therapies are required. Acidification of the tumor microenvironment drives the growth and metastasis of many cancers. Acid sensors such as acid-sensing ion channels (ASICs) may become promising targets for lung cancer therapy. Previously, we showed that inhibition of the ASIC1 channels by a recombinant analogue of mambalgin-2 from Dendroaspis polylepis controls oncogenic processes in leukemia, glioma, and melanoma cells. Here, we studied the effects and molecular targets of mambalgin-2 in lung adenocarcinoma A549 and Lewis cells, lung transformed WI-38 fibroblasts, and lung normal HLF fibroblasts. We found that mambalgin-2 inhibits the growth and migration of A549, metastatic Lewis P29 cells, and WI-38 cells, but not of normal fibroblasts. A549, Lewis, and WI-38 cells expressed different ASIC and ENaC subunits, while normal fibroblasts did not at all. Mambalgin-2 induced G2/M cell cycle arrest and apoptosis in lung adenocarcinoma cells. In line, acidification-evoked inward currents were observed only in A549 and WI-38 cells. Gene knockdown showed that the anti-proliferative and anti-migratory activity of mambalgin-2 is dependent on the expression of ASIC1a, α-ENaC, and γ-ENaC. Using affinity extraction and immunoprecipitation, mambalgin-2 targeting of ASIC1a/α-ENaC/γ-ENaC heteromeric channels in A549 cells was shown. Electrophysiology studies in Xenopus oocytes revealed that mambalgin-2 inhibits the ASIC1a/α-ENaC/γ-ENaC channels with higher efficacy than the ASIC1a channels, pointing on the heteromeric channels as a primary target of the toxin in cancer cells. Finally, bioinformatics analysis showed that the increased expression of ASIC1 and γ-ENaC correlates with a worse survival prognosis for patients with lung adenocarcinoma. Thus, the ASIC1a/α-ENaC/γ-ENaC heterotrimer can be considered a marker of cell oncogenicity and its targeting is promising for the design of new selective cancer therapeutics.

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Revealing molecular determinants governing mambalgin-3 pharmacology at acid-sensing ion channel 1 variants

Cristofori-Armstrong,

Budusan,

Smith

et al. 2024

Cell. Mol. Life Sci.

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Acid-sensing ion channels (ASICs) are trimeric proton-gated cation channels that play a role in neurotransmission and pain sensation. The snake venom-derived peptides, mambalgins, exhibit potent analgesic effects in rodents by inhibiting central ASIC1a and peripheral ASIC1b. Despite their distinct species- and subtype-dependent pharmacology, previous structure-function studies have focussed on the mambalgin interaction with ASIC1a. Currently, the specific channel residues responsible for this pharmacological profile, and the mambalgin pharmacophore at ASIC1b remain unknown. Here we identify non-conserved residues at the ASIC1 subunit interface that drive differences in the mambalgin pharmacology from rat ASIC1a to ASIC1b, some of which likely do not make peptide binding interactions. Additionally, an amino acid variation below the core binding site explains potency differences between rat and human ASIC1. Two regions within the palm domain, which contribute to subtype-dependent effects for mambalgins, play key roles in ASIC gating, consistent with subtype-specific differences in the peptides mechanism. Lastly, there is a shared primary mambalgin pharmacophore for ASIC1a and ASIC1b activity, with certain peripheral peptide residues showing variant-specific significance for potency. Through our broad mutagenesis studies across various species and subtype variants, we gain a more comprehensive understanding of the pharmacophore and the intricate molecular interactions that underlie ligand specificity. These insights pave the way for the development of more potent and targeted peptide analogues required to advance our understating of human ASIC1 function and its role in disease.

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Mambalgin-2 Inhibits Growth, Migration, and Invasion of Metastatic Melanoma Cells by Targeting the Channels Containing an ASIC1a Subunit Whose Up-Regulation Correlates with Poor Survival Prognosis

Cited by 13 publications

References 60 publications

Extracellular Vesicles Derived from Acidified Metastatic Melanoma Cells Stimulate Growth, Migration, and Stemness of Normal Keratinocytes

Extracellular Vesicles Derived from Acidified Metastatic Melanoma Cells Stimulate Growth, Migration, and Stemness of Normal Keratinocytes

Mambalgin-2 Inhibits Lung Adenocarcinoma Growth and Migration by Selective Interaction With ASIC1/α-ENaC/γ-ENaC Heterotrimer

Revealing molecular determinants governing mambalgin-3 pharmacology at acid-sensing ion channel 1 variants

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