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
Affiliations
Maksudbek Yusupov
Research Group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium
Angela Privat-Maldonado
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
Rodrigo M. Cordeiro
Centro de Ciências Naturais e Humanas, Universidade Federal Do ABC, Avenida Dos Estados 5001, CEP 09210-580, Santo André, SP, Brazil
Hanne Verswyvel
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
Priyanka Shaw
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
Jamoliddin Razzokov
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
Evelien Smits
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
Annemie Bogaerts
Research Group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium
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.
