Selective targeting of α7 nicotinic acetylcholine receptor by synthetic peptide mimicking loop I of human SLURP-1 provides efficient and prolonged therapy of epidermoid carcinoma in vivo

O V Shlepova; M A Shulepko; V O Shipunova; M L Bychkov; I D Kukushkin; I A Chulina; V N Azev; E I Shramova; V A Kazakov; A M Ismailova; Y A Palikova; V A Palikov; E A Kalabina; E A Shaykhutdinova; G A Slashcheva; E A Tukhovskaya; I A Dyachenko; A N Murashev; S M Deyev; M P Kirpichnikov; Z O Shenkarev; E N Lyukmanova

doi:10.3389/fcell.2023.1256716

Selective targeting of α7 nicotinic acetylcholine receptor by synthetic peptide mimicking loop I of human SLURP-1 provides efficient and prolonged therapy of epidermoid carcinoma in vivo

Front Cell Dev Biol. 2023 Oct 3:11:1256716. doi: 10.3389/fcell.2023.1256716. eCollection 2023.

Authors

O V Shlepova^#^{1

2}, M A Shulepko^#³, V O Shipunova^#^{2

4}, M L Bychkov¹, I D Kukushkin^{2

5}, I A Chulina⁶, V N Azev⁶, E I Shramova⁴, V A Kazakov⁶, A M Ismailova⁶, Y A Palikova⁶, V A Palikov⁶, E A Kalabina⁶, E A Shaykhutdinova⁶, G A Slashcheva⁶, E A Tukhovskaya⁶, I A Dyachenko⁶, A N Murashev⁶, S M Deyev^{4

7

8}, M P Kirpichnikov^{5

9}, Z O Shenkarev^{1

2

10}, E N Lyukmanova^{3

5

9}

Affiliations

¹ NTI Center, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
² Moscow Institute of Physics and Technology, National Research University, Dolgoprudny, Russia.
³ Faculty of Biology, Shenzhen MSU-BIT University, Shenzhen, China.
⁴ Immunology Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
⁵ Bioengineering Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
⁶ Branch of Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Pushchino, Russia.
⁷ Biomarker Research Laboratory, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.
⁸ Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.
⁹ Interdisciplinary Scientific and Educational School of Moscow University Molecular Technologies of the Living Systems and Synthetic Biology, Faculty of Biology, Lomonosov Moscow State University, Leninskie Gory, Moscow, Russia.
¹⁰ Structural Biology Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.

^# Contributed equally.

Abstract

α7-Type nicotinic acetylcholine receptor (α7-nAChR) promotes the growth and metastasis of solid tumors. Secreted Ly6/uPAR-Related Protein 1 (SLURP-1) is a specific negative modulator of α7-nAChR produced by epithelial cells. Here, we investigated mechanisms of antiproliferative activity of recombinant SLURP-1 in epidermoid carcinoma A431 cells and activity of SLURP-1 and synthetic 21 a.a. peptide mimicking its loop I (Oncotag) in a xenograft mice model of epidermoid carcinoma. SLURP-1 inhibited the mitogenic pathways and transcription factors in A431 cells, and its antiproliferative activity depended on α7-nAChR. Intravenous treatment of mice with SLURP-1 or Oncotag for 10 days suppressed the tumor growth and metastasis and induced sustained changes in gene and microRNA expression in the tumors. Both SLURP-1 and Oncotag demonstrated no acute toxicity. Surprisingly, Oncotag led to a longer suppression of pro-oncogenic signaling and downregulated expression of pro-oncogenic miR-221 and upregulated expression of KLF4 protein responsible for control of cell differentiation. Affinity purification revealed SLURP-1 interactions with both α7-nAChR and EGFR and selective Oncotag interaction with α7-nAChR. Thus, the selective inhibition of α7-nAChRs by drugs based on Oncotag may be a promising strategy for cancer therapy.

Keywords: A431; Ly6/uPAR; SLURP-1; cancer; lynx1; xenograft; α7-nAChR.

Copyright © 2023 Shlepova, Shulepko, Shipunova, Bychkov, Kukushkin, Chulina, Azev, Shramova, Kazakov, Ismailova, Palikova, Palikov, Kalabina, Shaykhutdinova, Slashcheva, Tukhovskaya, Dyachenko, Murashev, Deyev, Kirpichnikov, Shenkarev and Lyukmanova.

Grants and funding

The work was supported by Russian Science Foundation (project #23-74-00040). The animal breading, housing, toxicity and behavioral tests was supported by the Ministry of Science and Higher Education of the Russian Federation (Contract No 075-15-2021-1067).