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Current Evidence of the Role of the Myokine Irisin in Cancer

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Current Evidence of the Role of the Myokine Irisin in Cancer cancers Review Current Evidence of the Role of the Myokine Irisin in Cancer Evangelia Tsiani 1,2,*, Nicole Tsakiridis 1, Rozalia Kouvelioti 1,3, Alina Jaglanian 1 and Panagiota Klentrou 2,3 1 Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada; [email protected] (N.T.); [email protected] (R.K.); [email protected] (A.J.) 2 Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada; [email protected] 3 Department of Kinesiology, Brock University, St. Catharines, ON L2S 3A1, Canada * Correspondence: [email protected] Simple Summary: Regular exercise/physical activity is beneficial for the health of an individual and lowers the risk of getting different diseases, including cancer. How exactly exercise results in these health benefits is not known. Recent studies suggest that the molecule irisin released by muscles into the blood stream after exercise may be responsible for these effects. This review summarizes all the available in vitro/cell culture, animal and human studies that have investigated the relationship between cancer and irisin with the aim to shed light and understand the possible role of irisin in cancer. The majority of the in vitro studies indicate anticancer properties of irisin, but more animal and human studies are required to better understand the exact role of irisin in cancer. Abstract: Cancer is a disease associated with extreme human suffering, a huge economic cost to health systems, and is the second leading cause of death worldwide. Regular physical activity is associated with many health benefits, including reduced cancer risk. In the past two decades, exercising/contracting skeletal muscles have been found to secrete a wide range of biologically active proteins, named myokines. Myokines are delivered, via the circulation, to different cells/tissues, bind to their specific receptors and initiate signaling cascades mediating the health benefits of exercise. Citation: Tsiani, E.; Tsakiridis, N.; Kouvelioti, R.; Jaglanian, A.; Klentrou, The present review summarizes the existing evidence of the role of the myokine irisin in cancer. P. Current Evidence of the Role of the In vitro studies have shown that the treatment of various cancer cells with irisin resulted in the Myokine Irisin in Cancer. Cancers inhibition of cell proliferation, survival, migration/ invasion and induced apoptosis by affecting key 2021, 13, 2628. https://doi.org/ proliferative and antiapoptotic signaling pathways. However, the effects of irisin in humans remains 10.3390/cancers13112628 unclear. Although the majority of the existing studies have found reduced serum irisin levels in cancer patients, a few studies have shown the opposite. Similarly, the majority of studies have found Academic Editor: Justin C. Brown increased levels of irisin in cancer tissues, with a few studies showing the opposite trend. Clearly, further investigations are required to determine the exact role of irisin in cancer. Received: 1 April 2021 Accepted: 22 May 2021 Keywords: exercise; contraction; muscle; health benefits; myokines; irisin; cancer; in vitro; in vivo Published: 27 May 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- iations. Cancer is the leading cause of death worldwide, with an estimated 10 million deaths in 2020 [1]. This upward trend in global cases and mortality is influenced by potentially modi- fiable behaviors that are linked to cancer, such as smoking, poor diet, alcohol consumption and lack of exercise [2]. Cancer cells display enhanced growth rates and a resistance to programmed cell death termed apoptosis. In healthy cells, homeostasis and the mainte- Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. nance of normal tissue architecture is tightly controlled by cellular signaling cascades. In This article is an open access article cancer cells, mutations in key signaling molecules lead to homeostatic dysregulation [3–10]. distributed under the terms and Growth factor-initiated signaling cascades are activated when growth factors bind to their conditions of the Creative Commons receptors. These cascades are dysregulated in cancer cells, leading to enhanced prolifera- Attribution (CC BY) license (https:// tion and inhibition of apoptosis [5–11]. Enhanced growth factor signaling may be due to creativecommons.org/licenses/by/ increased growth factor production, receptor mutations or mutations in downstream key 4.0/). signaling molecules. Cancers 2021, 13, 2628. https://doi.org/10.3390/cancers13112628 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x 2 of 19 enhanced proliferation and inhibition of apoptosis [5–11]. Enhanced growth factor signal‐ ing may be due to increased growth factor production, receptor mutations or mutations Cancers 2021, 13, 2628 in downstream key signaling molecules. 2 of 19 The phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (Akt) pathway is heavily involved in cellular growth and homeostasis. This pathway is often mutated in many types of cancers and is implicated in deregulated cellular proliferation and apoptosis. Mu‐ The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway is heavily tated/activated Akt leads to tumorigenesis, as well as resistance to chemotherapy [12–15] involved in cellular growth and homeostasis. This pathway is often mutated in many and radiotherapy [16,17]. types of cancers and is implicated in deregulated cellular proliferation and apoptosis. Mu- The mammalian target of rapamycin (mTOR) and the ribosomal S6 kinase (p70 S6K) tated/activated Akt leads to tumorigenesis, as well as resistance to chemotherapy [12–15] areand activated radiotherapy downstream [16,17 of]. Akt, leading to increased protein synthesis and proliferation [5,7,18–21].The Activated mammalian Akt target also ofleads rapamycin to enhanced (mTOR) survival and theand ribosomal the inhibition S6 kinase of apoptosis (p70 S6K) [5].are Another activated signaling downstream molecule of that Akt, is leadingfrequently to mutated/activated increased protein synthesisin cancer is and Ras prolifer- [10]. Activatedation [5 Ras,7,18 leads–21]. to Activated the activation Akt of also mitogen leads‐ toactivated enhanced protein survival kinases and (MAPK), the inhibition result‐ of ingapoptosis in tumorigenesis [5]. Another and chemo signaling and molecule radiation that resistance is frequently [8]. mutated/activated in cancer isInitiation, Ras [10]. Activatedpromotion Ras and leads progression to the activation are the three of mitogen-activatedstages involved in proteinthe develop kinases‐ ment(MAPK), of cancer resulting [22]. Normal, in tumorigenesis healthy cells and acquire chemo and a series radiation of hallmark resistance capabilities, [8]. such as sustainingInitiation, proliferation, promotion evading and progression growth aresuppressors the three stagesand resisting involved cell in thedeath, development which enableof cancer them to [22 become]. Normal, malignant healthy [3,4]. cells acquire a series of hallmark capabilities, such as sustainingRegular physical proliferation, activity evading is associated growth suppressors with many health and resisting benefits cell and death, a reduced which enablerisk of manythem tocancers, become including malignant lung, [3,4 prostate]. and breast cancer [23–33]. Women who exercise regularlyRegular were found physical to have activity a significantly is associated decreased with many cancer health risk benefits [26,30,31,34]. and a reduced In addi risk‐ tion,of frequent many cancers, exercise including was found lung, to prostate increase and the breast survival cancer of breast [23–33 ].cancer Women patients who exercise [35]. Similarly,regularly regular were foundphysical to haveactivity a significantly was shown decreased to reduce cancerthe risk risk of lung [26,30 adenocarcinomas,31,34]. In addition, in frequentmen and exercise women was [23,24,29]. found to Despite increase this the epidemiological survival of breast evidence, cancer patients the exact [35]. mecha Similarly,‐ nismsregular involved physical in activity the anticancer was shown effects to reduce of regular the risk physical of lung adenocarcinomas activity/exercise inare men not and known.women [23,24,29]. Despite this epidemiological evidence, the exact mechanisms involved inRecent the anticancer evidence effects indicates of regular that physicalthe exercising activity/exercise muscle releases are not proteins known. called my‐ okines intoRecent the evidencebloodstream, indicates allowing that thethem exercising to be delivered muscle to releases different proteins tissues called in the myokines body andinto exert the the bloodstream, beneficial effects allowing of exercise them to be(Figure delivered 1). Prominent to different myokines tissues inproduced the body by and skeletalexert themuscle beneficial are interleukins effects of exercise‐6 and ‐ (Figure15 (IL‐16). and Prominent IL‐15), oncostatin, myokines produced myostatin, by brain skeletal‐ derivedmuscle neurotrophic are interleukins-6 factor (BDNF) and -15 and (IL-6 irisin and [36–38]. IL-15), oncostatin, myostatin, brain-derived neurotrophic factor (BDNF) and irisin [36–38]. Figure 1. Myokines mediate the health benefits of exercise. Muscle contractions induce the production Figureand 1. release Myokines of myokines mediate by the muscle, health benefits which are of deliveredexercise. Muscle through contractions the blood circulation induce the topro
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