Interleukin-6 Signaling in Triple Negative Breast Cancer Cells Elicits the Annexin A1/Formyl Peptide Receptor 1 Axis and Affects the Tumor Microenvironment

Lara Vecchi; Sara Teixeira Soares Mota; Mariana Alves Pereira Zóia; Isabella Castro Martins; Jessica Brito de Souza; Tiago Góss Santos; Adriano de Oliveira Beserra; Victor Piana de Andrade; Luiz Ricardo Goulart; Thaise Gonçalves Araújo

doi:10.3390/cells11101705

Interleukin-6 Signaling in Triple Negative Breast Cancer Cells Elicits the Annexin A1/Formyl Peptide Receptor 1 Axis and Affects the Tumor Microenvironment

Cells. 2022 May 20;11(10):1705. doi: 10.3390/cells11101705.

Affiliations

¹ Laboratory of Nanobiotechnology, Institute of Genetics and Biochemistry, Federal University of Uberlândia, Campus Umuarama, Bloco 2E, Sala 248, 38400-902 Uberlândia, Brazil.
² Laboratory of Genetics and Biotechnology, Federal University of Uberlândia, 38413-163 Patos de Minas, Brazil.
³ International Research Center, AC Camargo Cancer Center, 01509-900 São Paulo, Brazil.
⁴ Department of Investigative Pathology, AC Camargo Cancer Center, 01525-001 São Paulo, Brazil.

Abstract

Annexin A1 (AnxA1) is a pleiotropic protein that exerts essential roles in breast cancer (BC) growth and aggressiveness. In our previous work, we described the autocrine signaling of AnxA1 through formyl peptide receptor 1 (FPR1) in the triple-negative (TN) BC cell line, MDA-MB-231. Here, we aimed to describe the interaction between the AnxA1/FPR1 and the Interleukin-6 (IL-6) signaling pathways and their role in the tumor microenvironment (TME). First, we demonstrated that AnxA1 and IL-6 expression levels are correlated in BC tissue samples. In three TNBC cell lines, overexpression of both AnxA1 and IL-6 was also identified. Next, we inhibited FPR1, the IL-6 receptor and STAT3 in both MDA-MB-231 and MDA-MB-157 cells. The FPR1 inhibition led to increased levels of IL-6 and secreted AnxA1 in both cell lines. On the other side, inhibition of the IL-6 receptor or STAT3 led to the impairment of AnxA1 secretion, suggesting the essential role of the IL-6 signaling cascade in the activation of the AnxA1/FPR1 autocrine axis. Finally, we described the interaction between IL-6 and the AnxA1/FPR1 pathways and their role on the TME by analyzing the effect of supernatants derived from MDA-MB-231 and MDA-MB-157 cells under the inhibition of FPR1 or IL-6 signaling on fibroblast cell motility.

Keywords: Annexin A1; IL-6; STAT3; autocrine signaling; breast cancer; formyl peptide receptor.

Publication types

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

MeSH terms

Annexin A1* / metabolism
Humans
Interleukin-6 / metabolism
Receptors, Formyl Peptide / metabolism
Receptors, Interleukin-6 / metabolism
Triple Negative Breast Neoplasms* / metabolism
Tumor Microenvironment

Substances

Annexin A1
Interleukin-6
Receptors, Formyl Peptide
Receptors, Interleukin-6

Grants and funding

This research was funded by Fundação de Amparo a Pesquisa de Minas Gerais (FAPEMIG-Project APQ-00760-18 and REMITRIBIC RED-00031-21), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and the National Institute of Science and Technology in Theranostics and Nanobiotechnology-INCT–Teranano and Public Labour Prosecution Office (MPT-Patos de Minas), Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP-Projects 2015-02098-3 and 2009/14027-2).