Macrocyclic peptides targeting human CD44 inhibit cell adhesion

Cellular Signalling, vol. 136, pp. 112178

Abstract

CD44-hyaluronan interactions play a significant role in the progression of aggressive tumors. We generated non-native ligands for CD44 by identifying macrocyclic peptides that interact with the hyaluronan-binding domain of CD44. We investigated how the macrocyclic peptides L4-3 and D4-3 influence hyaluronan-engaged CD44 signaling in tumor cells, with a focus on glioma cells, as well as normal fibroblasts. Our findings indicated that inhibiting hyaluronan binding to CD44 in cultured U251MG glioma cells using the macrocyclic peptides L4-3 or D4-3 led to a reduction in cell adhesion and impacted various signaling pathways. The activation of hyaluronan-engaged CD44 during glioma progression - an aggressive and heterogeneous disease associated with multiple oncogenic alterations - cross-talk with epidermal growth factor receptor (EGFR) signaling. Specifically, the macrocyclic peptide L4-3 enhanced the negative feedback regulation of EGFR autophosphorylation at Tyr1068, an effect induced by phorbol 12-myristate 13-acetate (PMA). Furthermore, L4-3 inhibited EGF-mediated activation of the serine/threonine kinase AKT in glioma cells. These findings illuminate the relationship between the CD44-hyaluronan axis and EGFR signaling, suggesting a possible therapeutic strategy. Additionally, the macrocyclic peptide D4-3 suppressed hyaluronan-CD44-mediated adhesion and affected signaling related to cellular adhesion and migration in fibroblasts. However, it did not influence AKT and ERK1/2 signaling pathways. Thus, it is possible that the inhibitory effect of macrocyclic peptides L4-3 and D4-3 on hyaluronan-CD44 interaction have different effects in different cell types.

Authors 12

1. Athanasios Chatzopoulos

   Uppsala University · University of Patras

   Affiliation as printed

   Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden; Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece

2. Constantinos Kolliopoulos

   Uppsala University

   Affiliation as printed

   Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden

3. Yizhen Yin

   Shandong University · The University of Tokyo

   Affiliation as printed

   Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China

4. Theodoros T. Karalis

   Uppsala University

   Affiliation as printed

   Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden

5. Aya Komine

   University of Tsukuba

   Affiliation as printed

   Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, Ibaraki, Japan

6. Sophie Thi PhuongDung Tran

   University of Tsukuba

   Affiliation as printed

   Human Biology, School of Integrative and Global Majors, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan; Department of Experimental Pathology, Faculty of Medicine, University of Tsukuba, Japan

7. Jongchan Hwang

   St. Jude Children's Research Hospital · University of Tsukuba

   Affiliation as printed

   Human Biology, School of Integrative and Global Majors, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan; Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA; Department of Experimental Pathology, Faculty of Medicine, University of Tsukuba, Japan

8. Nohara Goto

   University of Tsukuba

   Affiliation as printed

   Human Biology, School of Integrative and Global Majors, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan; Asahi Kasei Pharma, Izunokuni-shi, Shizuoka, Japan; Department of Experimental Pathology, Faculty of Medicine, University of Tsukuba, Japan

9. Hiroaki Suga

   The University of Tokyo

   Affiliation as printed

   Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

10. Peter ten Dijke Aachen

    Leiden University · University of Tsukuba · Leiden University Medical Center · Oncode Institute

    Affiliation as printed

    Department of Cancer Signaling, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands

11. Christopher J. Hipolito corresponding

    University of Tsukuba

    Affiliation as printed

    Department of Cancer Signaling, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address: chris.john.hipolito@gmail.com

12. Paraskevi Heldin corresponding

    Uppsala University

    Affiliation as printed

    Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden. Electronic address: evi.heldin@imbim.uu.se