Oxidative damage to hyaluronan–CD44 interactions as an underlying mechanism of action of oxidative stress-inducing cancer therapy

Binding of the SARS-CoV-2 S-glycoprotein to cell receptors is vital for the entry of the virus into cells and subsequent infection. ACE2 is the main cell receptor for SARS-CoV-2, which can attach to the C-terminal receptor-binding domain (RBD) of the SARS-CoV-2 S-glycoprotein. The GRP78 receptor plays an anchoring role, which attaches to the RBD and increases the chance of other RBDs binding to ACE2. Although high levels of reactive oxygen and nitrogen species (RONS) are produced during viral infections, it is not clear how they affect the RBD structure and its binding to ACE2 and GRP78. In this research, we apply molecular dynamics simulations to study the effect of oxidation of the highly reactive cysteine (Cys) amino acids of the RBD on its binding to ACE2 and GRP78. The interaction energy of both ACE2 and GRP78 with the whole RBD, as well as with the RBD main regions, is compared in both the native and oxidized RBDs. Our results show that the interaction energy between the oxidized RBD and ACE2 is strengthened by 155 kJ/mol, increasing the binding of the RBD to ACE2 after oxidation. In addition, the interaction energy between the RBD and GRP78 is slightly increased by 8 kJ/mol after oxidation, but this difference is not significant. Overall, these findings highlight the role of RONS in the binding of the SARS-CoV-2 S-glycoprotein to host cell receptors and suggest an alternative mechanism by which RONS could modulate the entrance of viral particles into the cells.

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“… 20 It is known that RONS can cause oxidation and nitration of amino acids in proteins, which can disturb their normal functioning. 21 − 26 …”

Section: Introductionmentioning

confidence: 99%

Effect of Cysteine Oxidation in SARS-CoV-2 Receptor-Binding Domain on Its Interaction with Two Cell Receptors: Insights from Atomistic Simulations

Ghasemitarei

Privat-Maldonado

Yusupov

et al. 2021

J. Chem. Inf. Model.

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“…This correlates with the reduction of the number of Mia PaCa-2 cells present in the co-cultured tissue, which suggest that the reduction in weight is due to the elimination of Mia PaCa-2 cells. Although the reduction in the number of CD44 + Mia PaCa-2 cells could be due to a decrease in the expression of this marker, we have shown in a previous study that CAP increased the expression of CD44 in U87-MG and A375 cells [22]. It is likely that our findings correspond to the elimination of Mia PaCa-2 cells, rather than to the reduction of CD44 expression in PDAC cells.…”

Section: Discussionmentioning

confidence: 48%

“…CAP eliminates cancer cells via apoptosis, necrosis, ferroptosis, and immunogenic cell death, as shown in in vitro, in ovo, and in vivo models [16,[18][19][20], with less damaging effects on healthy cells [9,21]. The effect of CAP is not limited to only the cancer cells, as CAP can also oxidize ECM components, such as hyaluronan [22], and improve drug delivery in cancer [23][24][25]. In low doses, however, CAP-generated RONS can have positive effects, as CAP can boost wound healing and decontamination [26].…”

Section: Introductionmentioning

confidence: 91%

Cold Atmospheric Plasma Does Not Affect Stellate Cells Phenotype in Pancreatic Cancer Tissue in Ovo

Privat-Maldonado

Verloy

Delahoz

et al. 2022

IJMS

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Pancreatic ductal adenocarcinoma (PDAC) is a challenging neoplastic disease, mainly due to the development of resistance to radio- and chemotherapy. Cold atmospheric plasma (CAP) is an alternative technology that can eliminate cancer cells through oxidative damage, as shown in vitro, in ovo, and in vivo. However, how CAP affects the pancreatic stellate cells (PSCs), key players in the invasion and metastasis of PDAC, is poorly understood. This study aims to determine the effect of an anti-PDAC CAP treatment on PSCs tissue developed in ovo using mono- and co-cultures of RLT-PSC (PSCs) and Mia PaCa-2 cells (PDAC). We measured tissue reduction upon CAP treatment and mRNA expression of PSC activation markers and extracellular matrix (ECM) remodelling factors via qRT-PCR. Protein expression of selected markers was confirmed via immunohistochemistry. CAP inhibited growth in Mia PaCa-2 and co-cultured tissue, but its effectiveness was reduced in the latter, which correlates with reduced ki67 levels. CAP did not alter the mRNA expression of PSC activation and ECM remodelling markers. No changes in MMP2 and MMP9 expression were observed in RLT-PSCs, but small changes were observed in Mia PaCa-2 cells. Our findings support the ability of CAP to eliminate PDAC cells, without altering the PSCs.

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“…As is known, the availability of CD44 at the cell surface provides cancer cells with mechanisms of survival that perpetuate tumor growth. Modulating the levels of CD44 at the cell surface in cancer cells, as well as interaction with hyaluronan, is thus of great importance for cancer therapy, to disrupt the signaling pathways that favor tumor progression and pathology spreading [ 47 ]. Our data suggest that the delivery system itself works insofar it allows the internalization of DOX not from passive transport but via endocytic pathways, reaching some main organelles, such as lysosomes and mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Fluorescent Silica Nanoparticles Targeting Mitochondria: Trafficking in Myeloid Cells and Application as Doxorubicin Delivery System in Breast Cancer Cells

Sola

Montanari

Fiorani

et al. 2022

IJMS

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Fluorescent silica nanoparticles (SiNPs) appear to be a promising imaging platform, showing a specific subcellular localization. In the present study, we first investigated their preferential mitochondrial targeting in myeloid cells, by flow cytometry, confocal microscopy and TEM on both cells and isolated mitochondria, to acquire knowledge in imaging combined with therapeutic applications. Then, we conjugated SiNPs to one of the most used anticancer drugs, doxorubicin (DOX). As an anticancer agent, DOX has high efficacy but also an elevated systemic toxicity, causing multiple side effects. Nanostructures are usually employed to increase the drug circulation time and accumulation in target tissues, reducing undesired cytotoxicity. We tested these functionalized SiNPs (DOX-NPs) on breast cancer cell line MCF-7. We evaluated DOX-NP cytotoxicity, the effect on the cell cycle and on the expression of CD44 antigen, a molecule involved in adhesion and in tumor invasion, comparing DOX-NP to free DOX and stand-alone SiNPs. We found a specific ability to release a minor amount of CD44+ extracellular vesicles (EVs), from both CD81 negative and CD81 positive pools. Modulating the levels of CD44 at the cell surface in cancer cells is thus of great importance for disrupting the signaling pathways that favor tumor progression.

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Oxidative damage to hyaluronan–CD44 interactions as an underlying mechanism of action of oxidative stress-inducing cancer therapy

Cited by 48 publications

References 62 publications

Effect of Cysteine Oxidation in SARS-CoV-2 Receptor-Binding Domain on Its Interaction with Two Cell Receptors: Insights from Atomistic Simulations

Effect of Cysteine Oxidation in SARS-CoV-2 Receptor-Binding Domain on Its Interaction with Two Cell Receptors: Insights from Atomistic Simulations

Cold Atmospheric Plasma Does Not Affect Stellate Cells Phenotype in Pancreatic Cancer Tissue in Ovo

Fluorescent Silica Nanoparticles Targeting Mitochondria: Trafficking in Myeloid Cells and Application as Doxorubicin Delivery System in Breast Cancer Cells

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