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The Role of Irisin in Cancer Disease

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The Role of Irisin in Cancer Disease cells Review The Role of Irisin in Cancer Disease Agnieszka Pinkowska 1 , Marzenna Podhorska-Okołów 2, Piotr Dzi˛egiel 3,4 and Katarzyna Nowi ´nska 3,* 1 Department of Anatomy, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; [email protected] 2 Department of Ultrastructure Research, Wroclaw Medical University, 50-368 Wroclaw, Poland; [email protected] 3 Department of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; [email protected] 4 Department of Physiotherapy, University School of Physical Education, 51-612 Wroclaw, Poland * Correspondence: [email protected]; Tel.: +48-71-784-1354; Fax: +48-71-784-0082 Abstract: Irisin (Ir) is an adipomyokine that is involved in the regulation of metabolic processes. It also influences processes related to inflammation, including cancer. Initially, Ir was considered a hormone secreted by skeletal muscles in response to physical exercise. Further studies showed that Ir is also present in other healthy tissues, organs, and plasma. It influences the change in phenotype of white adipose tissue (WAT) into brown adipose tissue (BAT). It increases mitochondrial biogenesis and affects the expression of thermogenin (UCP1). This adipomyokine has also been found in many tumor tissues and in the serum of cancer patients. Studies are underway to determine the association between Ir and carcinogenesis. It has been confirmed that Ir inhibits in vitro proliferation, migration, and invasion. It is involved in the inhibition of epithelial–mesenchymal transition (EMT). Additionally, Ir affects the expression of the transcription factor Snail, which is involved in EMT, and inhibits transcription of the gene encoding E-cadherin, which is characteristic of epithelial-derived cells. Many studies have been performed to determine the role of Ir in physiological and pathological Citation: Pinkowska, A.; processes. Further detailed studies should determine more precisely the effect of Ir on the body in Podhorska-Okołów, M.; Dzi˛egiel,P.; health and disease. Nowi´nska,K. The Role of Irisin in Cancer Disease. Cells 2021, 10, 1479. Keywords: Irisin; FNDC5; cancer; proliferation; migration; epithelial–mesenchymal transition https://doi.org/10.3390/ cells10061479 Academic Editor: Debabrata Banerjee 1. Introduction Irisin (Ir) was first described in 2012 as a hormone released into the blood by skeletal Received: 13 May 2021 muscles in response to physical exercise. In their study, Boström et al. [1] found that an Accepted: 7 June 2021 Published: 12 June 2021 increase in the expression of fibronectin type III domain-containing protein 5 (FNDC5, a membrane protein) occurs under the influence of physical exercise in the muscle tissue. Fur- Publisher’s Note: MDPI stays neutral ther transformation of FNDC5 results in the formation of a new protein, known as Ir. This with regard to jurisdictional claims in process is controlled by the transcriptional coactivator peroxisome proliferator-activated published maps and institutional affil- receptor gamma coactivator 1 alpha (PGC1α). Boström et al. [1] assumed with high proba- iations. bility that other tissues could also be involved in the secretion of Ir. Multidirectional studies on Ir confirmed the primary assumptions of its discoverers. In addition to the primary localization, the expression of Ir has been found in other tissues and organs, i.e., in the adipose tissue [2,3], cardiomyocytes [4], kidney [4], liver [4], skin [4], and cerebellum [5]. FNDC5 is the precursor of Ir. In humans, this prohormone is encoded by the FNDC5 Copyright: © 2021 by the authors. FNDC5 Licensee MDPI, Basel, Switzerland. gene, which is located on chromosome 1 at position 35.1 (1p35.1). The gene consists This article is an open access article of six exons and five introns and spans 8.47 kbp [6]. Expression of this gene occurs under distributed under the terms and the influence of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α), conditions of the Creative Commons and the FNDC5 protein (also known as Frcp2 and PEP) is the product of its expression Attribution (CC BY) license (https:// (Figure1). The mass of the FNDC5 protein ranges from 20 to 32 kDa, and this difference is creativecommons.org/licenses/by/ related to post-translational modification [1]. FNDC5 is composed of a 29-amino-acid signal 4.0/). peptide, a 94-amino-acid fibronectin type III domain, a 28-amino-acid portion of unknown Cells 2021, 10, 1479. https://doi.org/10.3390/cells10061479 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 23 difference is related to post-translational modification [1]. FNDC5 is composed of a 29- Cells 2021, 10, 1479 2 of 22 amino-acid signal peptide, a 94-amino-acid fibronectin type III domain, a 28-amino-acid portion of unknown function (most likely Ir proteolytic cleavage site), a 19-amino-acid transmembrane domain, and a 39-amino-acid cytoplasmic domain [6,7]. function (most likely Ir proteolytic cleavage site), a 19-amino-acid transmembrane domain, and a 39-amino-acid cytoplasmic domain [6,7]. Figure 1. Structure of FNDC5 and Irisin. FNDC5 is composed of a 29-amino-acid signal pep- tide, a 94-amino-acid fibronectin type III domain, a 28-amino-acid domain (potential site of prote- olytic cleavage), a 19-amino-acid transmembrane domain, and a 39-amino-acid cytoplasmic domain. The diagram also shows the glycosylation site of Irisin by the formation of a bond between N- Figure 1. Structure of FNDC5 and Irisin. FNDC5 is composed of a 29-amino-acid signal peptide, a acetylglucosamine and the nitrogen originating from the amide group of asparagine (Asn36 and 94-amino-acid fibronectin type III domain, a 28-amino-acid domain (potential site of proteolytic cleavage),Asn81) a 19 and-amino subsequent-acid transmembrane dimerization ofdomain, Irisin molecules.and a 39-amino Irisin-acid is a ligandcytoplasmic for the domain. integrin The receptor. diagramPerhaps, also shows it also the works glycosylation by attaching site to of another Irisin by unknown the formation membrane of a bond receptor. between N-acetyl- glucosamine and the nitrogen originating from the amide group of asparagine (Asn36 and Asn81) and subsequentPost-transcriptional dimerization of Irisin processing molecules of. FNDC5 Irisin is a results ligandin for the the formation integrin receptor. of four Per- Ir isoforms haps,via it also alternative works by splicing.attaching Isoformto another 1 unknown (Q8NAU1-1) membrane is used receptor. as a canonical sequence. The other three isoforms, isoform 2 (Q8NAU1-2), isoform 3 (Q8NAU1-3), and isoform 4 (Q8NAU1-4), Posthave-transcriptional missing sequences processing of amino of acids FNDC5 at positions results in 182–212, the formation 1–75, and of 1–75,four Ir respectively isoforms [8]. via alternativeIn addition, splicing. biochemical Isoform studies 1 (Q8NAU1 have shown-1) is used that as Ir a cancanonical exist as sequence. a homodimer, The other and the threeFNIII-like isoforms, isoform domain 2 forms (Q8NAU1 a continuous-2), isoform intersubunit 3 (Q8NAU1β--sheet3), and dimer isoform [9]. 4 (Q8NAU1 Ir is formed- as 4), havea result missing of further sequences modifications of amino acids due toat cleavagepositions and 182– glycosylation212, 1–75, and of 1 the–75, extracellularrespec- tivelydomain [8]. In addition, of FNDC5 biochemical and contains studies 112 amino have acids shown [1]. that The Ir molecular can exist massas a homodimer, of Ir is estimated and theat 12FNIII kDa,-like although domain studies forms suggesta continuous that glycosylated intersubunitIr β- rangingsheet dimer from [9] 20. Ir to is 32 fo kDarmed is also as a resultsecreted of further [3]. Initial modifications studies showed due to remarkablecleavage and conservation glycosylation of of Ir the in mammals,extracellular which, domainaccording of FNDC5 to Boström and contains et al. 112 [1], amino implied acids its conserved [1]. The molecular function mass mediated of Ir is by estimated a cell surface at 12 receptor.kDa, although Further studies studies suggest showed that that glycosylated human FNDC5 Ir rangingis a gene from with 20 an to atypical 32 kDa startis also codon secretedto ATA [3]. Initial (encoding studies isoleucine) showed insteadremarkable of ATG conservation (encoding of methionine), Ir in mammals, which which, is present ac- in cordingthe to gene Boström in animals. et al. According[1], implied to its these conserved researchers, function using mediated this noncanonical by a cell surface start site is receptor.associated Further with studies the generation showed that of full-lengthhuman FNDC5 protein, is a whereas gene with the an start atypical of translation start co- at the don toATG ATA start (encoding codon results isoleucine) in the instead formation of ATG of a truncated(encoding isoform methionine), of Ir [10 which]. The is occurrence present of in theIr, gene which in isanimals. secreted According by skeletal to muscles these researchers, into human andusing mice this plasma noncanonical as a result start of physicalsite effort, and its potential influence on metabolism have generated much controversy. The is associated with the generation of full-length protein, whereas the start of translation at criticism was mostly related to the research methods. Erikson [7] indicated that several the ATG start codon results in the formation of a truncated isoform of Ir [10]. The occur- studies used antibodies that were irrelevant to Ir. Boström et al. [1] used a polyclonal rence of Ir, which is secreted by skeletal muscles into human and mice plasma as a result antibody against a peptide corresponding to C-terminal amino acids of the human FNDC5 (transmembrane segment) with no sequence from the Ir peptide. Similar objections were reported by Albrecht et al. [11] who paid attention to the variety of available assays for detecting and quantifying serum Ir. Due to their use, many studies were published in which Cells 2021, 10, 1479 3 of 22 serum Ir levels ranged from 0.01 to over 2000 ng/mL.
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