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 Table of Contents  
PERSPECTIVE ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 4  |  Page : 452-458

Hypothesized biological mechanisms by which exercise-induced irisin mitigates tumor proliferation and improves cancer treatment outcomes


1 Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
2 School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
3 Frimley Park Hospital, Camberley, United Kingdom
4 Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom
5 National Institute of Urology and Nephrology, Cairo, Egypt
6 Aberdeen Royal Infirmary, Aberdeen, United Kingdom

Date of Submission07-Sep-2021
Date of Acceptance08-Oct-2021
Date of Web Publication22-Dec-2021

Correspondence Address:
Dr. Chidiebere Emmanuel Okechukwu
Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5 – 00185 Rome.
Italy
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mgmj.mgmj_67_21

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  Abstract 

Exercise has been linked to a significant decrease in cancer pathogenesis. Irisin is an exercise-induced myokine that is released from the skeletal muscle upon cleavage of the membrane of fibronectin type III domain-containing protein 5. Exercise has been revealed to raise irisin concentration in the blood and muscle cells via the upregulation of peroxisome proliferator receptor γ coactivator-1α expression. Exercise-induced irisin reduces the risk of numerous cancers by burning excess body fat. We hypothesized that exercise-induced irisin may mitigate tumor proliferation by inducing apoptosis and improving cancer treatment outcomes via modulating several signaling and metabolic pathways, mainly by increasing the phosphorylation of adenosine monophosphate-activated protein kinase and acetyl-CoA-carboxylase, via deactivating the phosphatidylinositol 3-kinase/protein kinase B Snail signaling pathway, by upregulating the apoptosis pathway through the inhibition of epithelial–mesenchymal transition and via stimulating caspase activity.

Keywords: Adipocytes browning, apoptosis, cancer, exercise, irisin, physical activity


How to cite this article:
Okechukwu CE, Okechukwu CE, Agag A, Naushad N, Abbas S, Deb AA. Hypothesized biological mechanisms by which exercise-induced irisin mitigates tumor proliferation and improves cancer treatment outcomes. MGM J Med Sci 2021;8:452-8

How to cite this URL:
Okechukwu CE, Okechukwu CE, Agag A, Naushad N, Abbas S, Deb AA. Hypothesized biological mechanisms by which exercise-induced irisin mitigates tumor proliferation and improves cancer treatment outcomes. MGM J Med Sci [serial online] 2021 [cited 2022 Jan 18];8:452-8. Available from: http://www.mgmjms.com/text.asp?2021/8/4/452/333326




  Introduction Top


Physical activity (PA) is associated with significant reductions in cancer risk and progression. Irisin is an exercise-induced myokine that is released from the skeletal muscle upon cleavage of the membrane of fibronectin type III domain-containing protein 5 (FNDC5).[1] Exercise has been revealed to increase irisin concentration in the blood and muscle cells via the upregulation of peroxisome proliferator receptor γ coactivator-1α (PGC-1α) expression.[2] The plasma level of irisin increases after exercise. Irisin is extensively distributed in the human body, and it is involved in the conversion of white adipose tissue (WAT) to brown adipose tissue (BAT). BAT contains a large concentration of uncoupling protein-1 (UCP1), which can dissipate the energy produced by oxidation in the mitochondria as heat energy, thus encouraging energy consumption and regulation of energy metabolism.[1]

Irisin induced G2/M cell cycle arrest and increased cyclin-dependent kinase inhibitor 1 levels in glioblastoma cells, causing the inhibition of cell proliferation. Irisin subdued glioblastoma cell invasion by upregulating tissue factor pathway inhibitor-2 and overturning the hostile tumor phenotype.[3] Irisin induced G1 arrest in pancreatic cancer cell lines, hence inhibiting the proliferation of pancreatic cancer cells. Irisin overturned the activity of the epithelial–mesenchymal transition (EMT), triggered the adenosine monophosphate-activated protein kinase (AMPK) pathway, and lowered the mammalian target of rapamycin signaling (mTOR). Irisin upregulated the apoptosis pathway by inhibiting EMT and stimulating caspase activity.[4] Irisin induced the apoptosis of malignant breast cancer cells through activation of caspase-3 and caspase-7.[5] Several signaling cascades were induced or deactivated in various cancer cells upon irisin treatment. Inhibition of EMT by irisin could reinstate apoptosis capability in lung and pancreatic cancer cells. Moreover, irisin may increase apoptosis by increasing the phosphorylation of AMPK and acetyl-CoA-carboxylase.[6] A higher level of physical fitness was connected to a rise in post-exercise irisin concentration when compared with a lower fitness level after an acute bout of exercise in healthy adults.[7] Individualized and supervised exercise routines are the standard mode of training for patients with cancer during and after treatment to mitigate cancer-related fatigue, cancer-treatment-induced cardiovascular toxicity, and cognitive impairment.[8],[9]

Physiological features of exercise-induced irisin

Irisin was primarily defined in 2012 as a hormone that is secreted from the muscle cells of transgenic mice expressing PGC-1α, which plays an important role in numerous pathways associated with energy metabolism.[10] A high concentration of circulating irisin, which is cleaved from its precursor FNDC5, was linked to improved glucose homeostasis by decreasing insulin resistance. In humans, FNDC5 is majorly expressed in skeletal muscles and in other organs that contain muscles, such as the heart, tongue, and rectum. On the contrary, the expression of FNDC5 is at a lower level in the pancreas and liver, which are key organs involved in glucose homeostasis. In rats, irisin is released from matured adipocytes of WAT, mostly in subcutaneous adipose tissue and less in visceral adipose tissue.[11] Apart from the skeletal and cardiac muscles, irisin has also been found in the neurons, neuroglia cells in the brain, sebaceous glands in the skin, and slightly in the liver, pancreas, spleen, stomach, and testis of rats.[12] Circulating irisin is excreted mainly through the hepatobiliary system and the kidney.[13]

In humans, the type, duration, and intensity of exercise appear to be essential for modifications in the circulating levels of irisin. Both aerobic exercise and resistance/strength training increase the circulating levels of irisin.[14] Engaging in moderate-intensity exercise over a long period leads to a significant elevation of irisin levels, with a significant decrease in body mass index, waist circumference, and fasting blood glucose levels.[15] However, elevated peak oxygen consumption and ventilatory efficiency are linked to improved activity of FNDC5 in the muscle.[16]

Irisin ignites the browning of WAT and thermogenesis by activating UCP1.[17] However, inhibition of irisin gene expression decreased UCP1 expression and increased adipogenesis, which is prevalent in obesity.[18] Thus, the inhibitory effects of irisin on adipogenesis highlight its role in direct signaling from skeletal muscle to BAT.[19] Moreover, BAT has a larger number of mitochondria and improved energy expenditure because of its high oxygen consumption, and it accumulates fewer lipids than WAT.[20] However, WAT mainly stores energy as triglycerides, while BAT is well-known for dissipating energy via uncoupled mitochondrial respiration and hence performs a vital role in the regulation of body weight. This is facilitated by UCP1 which is robustly expressed in BAT.[19],[20] Both recombinant irisin-treated cells and FNDC5-overexpressed cells triggered an inhibition of adipogenesis which was demonstrated by the downregulation of CCAAT-Enhancer-binding Protein α, peroxisome proliferator-activated receptor-gamma, and fatty acid-binding protein 4 expressions and decreased lipid build-up.[21] The inhibitory effect of irisin on adipogenesis is facilitated by the activation of Wnt expression, which is known to regulate mesenchymal stem cells and control adipogenesis.[21] Practically, both exogenous and endogenous irisin inhibit adipogenesis. Irisin functions as a biological defensive factor against obesity, which is a risk factor for cancer. This is facilitated by irisin-induced browning of WAT, therefore regulating excessive regional fat deposition.[22] Irisin plays a vital role in the prevention of obesity and metabolic imbalances in insulin resistance and type 2 diabetes by stimulating browning of WAT, improving glucose uptake in skeletal muscle and the heart, enhancing hepatic glucose and lipid metabolism, and increasing pancreatic beta-cell function.[23]

Hypothesis

We hypothesized that exercise-induced irisin may mitigate tumor proliferation by inducing apoptosis and improving cancer treatment outcomes via modulating several signaling and metabolic pathways, mainly by increasing the phosphorylation of AMPK and acetyl-CoA-carboxylase, via deactivating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) Snail signaling pathway, by upregulating the apoptosis pathway through the inhibition of EMT and via stimulating caspase activity.

Studies that support the hypothesis

Patients with bladder cancer had significantly lower levels of serum irisin, and the higher the stage of bladder cancer, the lower the levels of serum irisin.[24] Serum levels of irisin were significantly lower in breast cancer patients compared to controls.[24] It was estimated that a single unit rise in irisin levels reduces the risk of breast cancer.[25] Thus, exercise intervention is vital during the treatment of different stages of cancer due to the role of physical exercise in the regulation of irisin. Shao et al.[26] examined whether irisin could decrease the occurrence of lung cancer, and they found that irisin inhibited EMT and decreased the invasion of lung cancer cells via the alteration of the PI3K/AKT Snail signaling pathway. The movement and invasive capacity of lung cancer cells could be regulated by irisin through the inhibition of the PI3K/AKT Snail signaling pathway and suppression of EMT.[26] These findings demonstrate that engaging in regular PA has the potency to mitigate lung cancer and its progression. The PI3K/AKT signaling pathway is involved in numerous cellular processes, such as cell proliferation, differentiation, survival, and death. The expression and activity of PI3K and AKT are upregulated in pancreatic cancer cells.[27] Moreover, the PI3K/AKT signaling pathway is an important regulatory pathway that can serve as a therapeutic target in the treatment of numerous cancers. Irisin decreased the movement and infiltration of lung cancer cells by blocking the PI3K/AKT signaling pathway.[26] Irisin enhanced the number and activity of endothelial progenitor cells via suppressing the PI3K/AKT signaling pathway, hence decreasing the levels of the AKT protein in BxPC-3 cells.[27] Irisin mitigates pancreatic cancer cell growth through the AMPK-mTOR signaling pathway, and this indicates that irisin is capable of initiating tumor cell apoptosis, which is a vital cellular mechanism through which anti-cancer medications exert their restorative effects.[27] Irisin initiates apoptosis in pancreatic cancer cells, and this is linked with the modification of B-cell lymphoma 2 associated X, apoptosis regulator, and B-cell lymphoma 2 (Bcl-2) protein expression.[27] Irisin altered the activity of the PI3K/AKT signaling pathway by communicating with the Bcl-2 family.[27] Irisin modified the cytotoxicity of doxorubicin in pancreatic cancer cells mainly through deactivating the PI3K/AKT/NF-kappaB signaling pathway.[28] One study found that irisin treatment substantially inhibited the proliferation, migration, and invasion of osteosarcoma cells.[29] Irisin overturned the Interleukin 6 (IL-6)-induced EMT in osteosarcoma cells by modulating the expression of E-cadherin, N-cadherin, vimentin, fibronectin, matrix metalloproteinase-2, 7, and 9.[29] Irisin suppresses IL-6-activated phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the expression of Snail in osteosarcoma cells and the obstruction of STAT3 by WP1066.[29] Moreover, a STAT3 inhibitor additionally improved the effects of irisin on EMT and Snail expression in osteosarcoma cells.[29] Mazur-Bialy et al.[30] assessed the effects of exercise-inducible irisin on tumor growth and progression, and they found inhibition of anchorage-dependent and anchorage-independent cell growth complemented by a rise in cell apoptosis in a dose and the time-reliant way in breast cancer cell lines treated with irisin. The cell movement and invasion through the extracellular matrix were weakened by irisin at 50 and 100 Nm, respectively.[30] There were improvements in the expression of checkpoint kinase 2, ATM serine/threonine kinase, breast cancer type 2, E2F transcription factor 4, histone deacetylase 2 and 9 genes which relate to the inhibition of tumor growth and its progression when cancer cells were treated with high irisin concentration at 100 nm. Moreover, reductions in the expression of protooncogene polo-like kinase 1, e2f transcription factor 1, growth arrest and deoxyribonucleic acid damage-inducible beta, histone deacetylase 5 and 6, and swi/snf related, matrix associated, actin-dependent regulator of chromatin, subfamily a, member 2 were observed.[30] These findings demonstrate that exercise-induced irisin could be a possible anti-cancer agent.[30] Furthermore, exercise-induced irisin may be efficacious in the prevention of tumor proliferation by modifying various signaling pathways associated with cancer pathogenesis, metabolism, and progression. Cancer rehabilitation is an essential therapeutic plan in the treatment and care of patients with cancer and post-cancer patients. The key objectives of cancer rehabilitation are to increase cardiopulmonary fitness/functional capacity, musculoskeletal function, metabolic health, quality of life, emotional wellbeing, and cognitive functions among cancer survivors.[31] Aerobic exercise and strength training increases the level of irisin in both healthy and obese adults [Table 1].[32],[33],[34],[35],[36] Exercise promotes irisin gene expression, which has a significant influence on thermogenesis, and this manifests as enhanced gene expression of proteins such as UCP-1, which is associated with the browning of WAT.[37] The browning of WAT leads to an increase in energy expenditure, thus enhancing obesity prevention and treatment.[37] Tsuchiya et al. stated that resistance training triggered a high increase in irisin concentration compared to endurance exercise under corresponding exercise duration.[38] Nygaard et al. found that single sessions of intense endurance exercise and heavy strength training led to a transitory increase in irisin concentrations in the blood, but this was not complemented by an increase in FNDC5 expression.[39] Irisin response to resistance exercise is higher in individuals with a lower proportion of lean body mass.[39] The levels of irisin in the blood were significantly increased following resistance training in both old mice and humans.[40] An increase in circulating irisin levels stimulated by resistance training was associated with an increase in physical performance.[41] Short bouts of vigorous-intensity exercise rapidly improved serum irisin levels among obese adolescents.[42]
Table 1: Effect of exercise type and intensity on irisin levels in healthy and obese adults

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  Discussion Top


Exercise interventions during and after cancer treatment are effective in improving the quality of life, physical, and mental health among cancer survivors.[43] Patients with lung cancer can attain considerable improvements in physical fitness after the completion of an exercise program.[43] Obesity is a common risk factor for cancer because obesity leads to a rise in inflammatory markers, mainly IL-6 and Tumor Necrosis Factor Alpha (TNF-α).[44] Obesity also increases insulin resistance, and adipokine secretions and these markers support tumor survival and proliferation.[45] On the other hand, physical exercise exerts anti-inflammatory effects by decreasing the expression of TNF-α and other inflammatory cytokines.[46] Exercise decreases obesity by increasing irisin levels. Exercise-induced irisin may be used as a biological marker for the metabolic response to exercise in obese people and to monitor reductions in cancer risk linked to obesity. Exercise-induced irisin may reduce cancer proliferation by decreasing cell migration and possibly reverse cancer resisting cell death by upregulating caspase-3 activity and consequently inducing apoptosis.[47] Moreover, in vitro studies have revealed a decrease in the number of malignant tumor cells as well as enhanced caspase-3 and -7 activity in conjunction with NF-B inhibition after irisin treatment.[48]

Irisin has been demonstrated to have protective effects on bone health, and these bone-protective effects induced by irisin defend the bones from cancer metastasis, thus proving irisin’s capability in mitigating cancer proliferation and metastasis.[49],[50] Apart from the role of exercise in improving the circulating levels of irisin, the influence of exercise on cancer pathogenesis is also based on its efficacy in modulating inflammatory cytokines, immune function, sex steroids, Insulin-like growth factor-1, insulin, and adipokines.[51] Zarei et al., recently discovered that irisin treatment inhibited the proliferation, migration, and invasion of ovarian cancer cells.[52] Irisin also triggered apoptosis in ovarian cancer cells. Through the Hypoxia-inducible factor-1, irisin regulated the expression of genes involved in aerobic respiration in ovarian cancer cells.[52]

Obesity increased breast cancer risk in postmenopausal women in a nonlinear dose-response approach, and it is important to recognize that weight control may be a critical component in reducing breast cancer susceptibility.[53] However, favorable tumor growth and metastasis require communication between tumor cells and the nearby tissues. Because of the abundant features of adipose tissue, many types of tumors nurture and survive close to adipocytes and adipose-linked stromal and vascular areas, such as connective cells including fibroblasts, stem/progenitor cells, endothelial cells, innate and adaptive immune cells, and extracellular signaling and matrix zones.[54] Thus, excess adiposity increases the risk of cancer. Moreover, irisin upregulates the expression of Ucp1 and Type II iodothyronine deiodinase, which are two main proteins involved in adipose tissue thermogenesis, hence substantiating the beneficial roles of exercise-induced irisin in the prevention and treatment of obesity, thus decreasing the risk of cancer.[23] Therefore, exercise-induced irisin may prevent tumor proliferation, and as well reduce the risk of numerous cancers by burning excess body fat, and by regulating adipocytes and adipose tissues.[55] However, the exact exercise protocol that can be tailored for patients during cancer treatment to enhance the effects of irisin on tumor proliferation and fat metabolism is yet to be identified. Therefore, during cancer treatment, the medical oncologist and rehabilitation specialists, which consist of a certified clinical exercise physiologist and physiotherapist, should tailor, and prescribe PA according to a patient’s functional capacity and cardiometabolic health.[56],[57] Moreover, it is important to monitor a patient’s tolerance and adaptation to the personalized exercise routine.


  Conclusion Top


Exercise-induced irisin may decrease the risk of tumor proliferation by inducing apoptosis and improve cancer treatment outcomes by modulating several signaling pathways, mostly by increasing the phosphorylation of AMPK and acetyl-CoA-carboxylase, via deactivating the PI3K/AKT signaling pathway, via upregulating the apoptosis pathway through the inhibition of EMT and by stimulating caspase activity. Therefore, there is a need for physicians to design, tailor/personalize, and prescribe PA for patients with cancer undergoing treatment. Moreover, adherence to a regular strength training routine significantly increased the production of irisin among healthy and obese adults, and this is a potential benefit of resistance training during rehabilitation for cancer survivors. Exercise is effective in improving physical and cardio-metabolic health among cancer survivors. Irisin plays an important role in the prevention, diagnosis, and treatment of cancer. Hence, analyzing the levels of PA and the expression of irisin among patients with cancer may be of immense help in the treatment of numerous cancers. However, further studies are required to investigate the role of exercise-induced irisin in autophagy, and the receptors, pathways, and mechanisms involved.

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Conflicts of interest

There are no conflicts of interest.



 
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