AUTHOR=Shlepova O. V. , Shulepko M. A. , Shipunova V. O. , Bychkov M. L. , Kukushkin I. D. , Chulina I. A. , Azev V. N. , Shramova E. I. , Kazakov V. A. , Ismailova A. M. , Palikova Y. A. , Palikov V. A. , Kalabina E. A. , Shaykhutdinova E. A. , Slashcheva G. A. , Tukhovskaya E. A. , Dyachenko I. A. , Murashev A. N. , Deyev S. M. , Kirpichnikov M. P. , Shenkarev Z. O. , Lyukmanova E. N. TITLE=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 JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=11 YEAR=2023 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2023.1256716 DOI=10.3389/fcell.2023.1256716 ISSN=2296-634X 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.