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

Maksudbek Yusupov; Angela Privat-Maldonado; Rodrigo M Cordeiro; Hanne Verswyvel; Priyanka Shaw; Jamoliddin Razzokov; Evelien Smits; Annemie Bogaerts

doi:10.1016/j.redox.2021.101968

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

Redox Biol. 2021 Jul:43:101968. doi: 10.1016/j.redox.2021.101968. Epub 2021 Apr 11.

Authors

Maksudbek Yusupov¹, Angela Privat-Maldonado², Rodrigo M Cordeiro³, Hanne Verswyvel⁴, Priyanka Shaw⁴, Jamoliddin Razzokov⁵, Evelien Smits⁶, Annemie Bogaerts⁷

Affiliations

¹ Research Group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium. Electronic address: maksudbek.yusupov@uantwerpen.be.
² Research Group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium; Solid Tumor Immunology Group, Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium. Electronic address: angela.privatmaldonado@uantwerpen.be.
³ Centro de Ciências Naturais e Humanas, Universidade Federal Do ABC, Avenida Dos Estados 5001, CEP 09210-580, Santo André, SP, Brazil.
⁴ Research Group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium; Solid Tumor Immunology Group, Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
⁵ Research Group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium; Tashkent Institute of Irrigation and Agricultural Mechanization Engineers, Kori Niyoziy 39, 100000, Tashkent, Uzbekistan; Institute of Material Sciences, Uzbek Academy of Sciences, Chingiz Aytmatov 2b, 100084, Tashkent, Uzbekistan.
⁶ Solid Tumor Immunology Group, Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
⁷ Research Group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium. Electronic address: annemie.bogaerts@uantwerpen.be.

Abstract

Multiple cancer therapies nowadays rely on oxidative stress to damage cancer cells. Here we investigated the biological and molecular effect of oxidative stress on the interaction between CD44 and hyaluronan (HA), as interrupting their binding can hinder cancer progression. Our experiments demonstrated that the oxidation of HA decreased its recognition by CD44, which was further enhanced when both CD44 and HA were oxidized. The reduction of CD44-HA binding negatively affected the proliferative state of cancer cells. Our multi-level atomistic simulations revealed that the binding free energy of HA to CD44 decreased upon oxidation. The effect of HA and CD44 oxidation on CD44-HA binding was similar, but when both HA and CD44 were oxidized, the effect was much larger, in agreement with our experiments. Hence, our experiments and computations support our hypothesis on the role of oxidation in the disturbance of CD44-HA interaction, which can lead to the inhibition of proliferative signaling pathways inside the tumor cell to induce cell death.

Keywords: Binding free energy; Cancer therapies; Cell proliferation; Hyaluronan-CD44 interaction; Oxidative stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Hyaluronan Receptors
Hyaluronic Acid*
Neoplasms*
Oxidative Stress
Signal Transduction

Substances

Hyaluronan Receptors
Hyaluronic Acid