Abstract
In the last few decades, there has been notable progress in understanding the molecular and cellular basis of the complex process involved in cancer. In this context, tumor-promoting inflammation, dysregulation of apoptotic signaling, tissue invasion and metastasis, and cancer microenvironment have recently attracted interest from researchers. Irisin is a hormone released by muscles during exercise and it directly acts on key functional cells involving energy metabolism and homeostasis. Recently, many studies have reported the anticancer effect of irisin against different types of cancer. Translation of these findings to clinical practice for the diagnosis and treatment of several types of cancer is urgently required. In this review, we summarized preclinical and clinical studies on the anticancer effects of irisin in various types of cancer, and also discussed the mechanisms activated by irisin to suppress cancer pathogenesis. We further discussed the serum level of irisin related to different types of cancer to understand more clearly the association between irisin concentration and tumor burden. This review may serve as a solid foundation for researchers and physicians to support basic and clinical studies on irisin as a promising strategy for early diagnosis and treatment of a various types of cancers.
Introduction
Cancer is defined as an indulgent growth of abnormal cells in the body. It is one of the deadliest public health problems around the globe and is the second leading cause of mortality in the United States. 1 In 2018, an epidemiological study disclosed that the most frequent causes of cancer death are lung, prostate, and colorectal cancers (CRCs) in men; and lung, breast, and CRCs in women. 1 These four types of cancers account for 45% of all cancer deaths. 1 Despite the genetic hallmarks of cancer, lifestyle and environmental factors play a crucial role in the development of cancer. 2 Indeed, overweight, obesity, and physical inactivity are responsible for the development of several kinds of cancers. 3 Vainio et al. 3 suggested that physical activity inversely correlated with the risk of breast and colon cancers. Furthermore, previous multiple studies demonstrated that physical activity also minimizes the risk of endometrial and ovarian cancer, and decreased the incidence of lung cancer.4,5 Physical activity can regulate the secretion of several hormones, including estrogen, insulin, 6 and irisin. 7
Irisin, a recently discovered exercise hormone is believed to be released from skeletal muscle during exercise, and is considered as a crucial therapeutic agent in a wide variety of metabolic diseases. 7 Although concentrations of circulating irisin are interrelated with lean body mass and may be elevated by exercise or cold exposure stress, the mechanism of irisin secretion remains controversial.7–9 Since irisin efficiently triggers metabolism and mitochondrial biogenesis in adipocytes and myocytes, it has gained a great deal of attention in the scientific fields.7,10 Irisin is known to regulate metabolism and may have specific effects on cancers that are induced by metabolic disorders. Although irisin was initially identified in skeletal muscle and adipose tissue, 11 it has also been identified in the brain, pancreas, liver, stomach, 12 heart, 13 spleen, and skin. 14 Besides, recent studies revealed that irisin expression is increased in metabolic disorder patients, 15 cervical cancer, endometrial cancer, 16 cancer cachexia, 17 and prior gestational diabetes mellitus. 18 Conversely, expression of irisin is reduced in patients with type 2 diabetes19,20 and non-alcoholic fatty liver disease. 21 Most recent studies have demonstrated that serum irisin concentration is reduced in patients with breast cancer, 22 and it exerts inhibitory effect on malignant breast cancer cells. 23
In this review, the preclinical (Table 1) and clinical (Table 2) evidences regarding the anticancer efficacy of irisin in humans are discussed. However, the relationship between irisin and cancer is poorly understood. Therefore, herein we discussed the serum irisin levels associated with different types of cancer to clearly understand the association between irisin concentration and tumorigenesis (Table 3).
Preclinical studies of irisin on different types of cancer.
TNF-α: tumor necrosis factor alpha; EMT: epithelial–mesenchymal transition; STAT3: signal transducer and activator of transcription 3; IL-6: interleukin-6; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinase B.
Clinical studies of irisin on different types of cancer.
FNDC5: fibronectin type III domain-containing protein 5; CEA: carcinoembryonic antigen; HCC: hepatocellular carcinoma; SCD-1: stearoyl-CoA desaturase; NOTCH1: Notch homolog 1; IL-6: interleukin-6; TNF-α: tumor necrosis factor alpha; CRC: colorectal cancer.
Comparison of serum irisin levels between healthy and cancer subjects in various cancer types.
Molecular mechanism of irisin in cancer
Role of irisin in tumor-promoting inflammation
Cumulative evidences have suggested that chronic inflammation and cancer development are interrelated.33,34 Interestingly, inflammation can directly promote cancer growth and development by generating a wide array of inflammatory molecules including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), hypoxia-inducible factor-1α (HIF-1α), signal transducer and activator of transcription-3 (STAT3), pro-inflammatory molecules such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-23 (IL-23), interleukin-1β (IL-1β).34,35 In addition, components of the chemokine framework influences various pathways of tumor development, including leukocyte recruitment, neo-angiogenesis, tumor cell proliferation and survival, invasion, and metastasis. 36
Fibronectin type III domain-containing protein 5 (FNDC5), the precursor of irisin, is a type-1 membrane protein. It has been reported that only low levels of FNDC5/irisin mRNA remain in noncancerous hepatic tissue. 31 This study confirmed the overexpression of irisin in patients with hepatocellular carcinoma (HCC), leading to the gene expression of mediators that engaged in lipogenesis, inflammation, and carcinogenesis as well. 31 Gaggini et al. 31 reported hepatic FNDC5/irisin mRNA expression has been notably elevated in patients with HCC compared with the normal group, and they also observed a solid transcriptional relevance including sterol regulatory element binding transcription factor 1 (SREBF-1)/SCD-1 (stearoyl-CoA desaturase-1), TNF-α/IL-6, and Notch homolog 1 (NOTCH1), which are hallmarks of lipogenesis, inflammation, and tumorigenesis. This result suggests that induction of FNDC5/irisin expression might play a protective role in carcinogenesis in liver. FNDC5/irisin expression is additionally associated with the de novo lipogenesis (DNL) index and lipid profile. 31 Thus, the results proposed that irisin secreted as a paracrine hormone during hepatic cancer development was responsible for DNL inhibition. In HCC patients, in whom hepatic DNL is upregulated, the overexpression of FNDC5/irisin could imply a compensatory mechanism to embargo lipogenesis prompted by cancer development. 31 Thus, the preliminarily consequences of this investigation recommend that the induction of FNDC5/irisin expression might be a potential therapeutic strategy for the treatment of metabolic disorder and carcinogenesis.
Furthermore, FNDC5/irisin, TNF-α, IL-1, and IL-6 levels were increased by experimentally induced gastric cancer in mice. 17 Previous study demonstrated that serum concentration of irisin in patients with breast cancer were notably lower compared with that of control. 22 In addition, it has enumerated that one single unit escalation of irisin concentration leading to a reduction in the possibility of breast cancer by nearly 90%. 22 More specifically, irisin significantly inhibits NF-κB activity on breast cancer cells, which indicated irisin is a potent anti-inflammatory molecule that may offer the therapeutic opportunity to care for breast cancer. 23 Kong et al. 24 also reported that irisin effectively reversed the IL-6-induced epithelial-mesenchymal transition (EMT) in osteosarcoma cells.
Further studies are required to evaluate the direct pro/anti-inflammatory properties of irisin in various cancers while considering irisin-induced cachexia. It is important to characterize changes in irisin in the circulation with the development of cancer before irisin can be implemented as a therapeutic agent.
Role of irisin in dysregulation of the apoptosis pathway
Apoptosis is one of the highest studied subjects among cell biologist. 37 Understanding apoptosis in particular diseases condition is crucial because it not only provides the knowledge of disease pathogenesis but also gives clues on how to treat the diseases. 37 In cancer, the balance between cell division and cell death is disrupted, and cancer cells also overlook the signals that can cause them to halt driving. Previous studies have established that up-regulation of p53, a tumor suppressor gene, discourages tumor growth and development, 38 and is considered to play a critical role in several human cancers such as breast, 39 colorectal, 40 and pancreatic cancer. 41 In addition, activation of PI3K/Akt pathway can decelerate p53-mediated apoptosis. 42
Irisin has been shown to exert an extensive inhibitory effect on cell number and migratory characteristics in malignant breast cancer cells, without influencing nonmalignant cells. 23 The researchers observed irisin-initiated apoptosis of malignant breast cancer cells via activation of caspase-3 and caspase-7. 23 Numerous studies have embroiled the contribution of PI3K and Akt in cell cycle regulation, apoptosis, and malignant transformation. 43 Shao et al. 26 demonstrated that irisin effectively reversed EMT activity and suppressed the Snail via PI3K/Akt signaling pathway in lung cancer cells. On the contrary, a study investigating obesity-related cancer cell lines originating from endometrial, colon, thyroid, and esophageal cancer reported no critical role of irisin in the regulation of cell adhesion, proliferation, or malignancy. 25 However, this imbalance may be a function of different experimental techniques or cell types. Irisin in prostate cancer cells may have cytotoxic effects on androgen receptors in a dose-dependent manner. 28 Although irisin does not affect obesity-related cancer cell lines, it suppresses other types of cancer such as breast, lung, and prostate. In conclusion, irisin may play an important role as a cancer therapeutic by regulating different signaling pathways, including inhibition of EMT and stimulation of caspase activity (Figure 1).
Schematic diagram of irisin modulation apoptosis mechanisms on different cancer cells. Multiple signaling cascades are induced or inactivated in different cancer cells upon irisin treatment. In breast cancer cells, irisin increases apoptosis by stimulating caspase activity. Inhibition of EMT could restore apoptosis capacity. Irisin can restore apoptosis by inhibiting EMT in both lung and pancreatic cancer cells. Activation of AMPK in HCC was found to be associated with mitochondrial dysfunction and subsequent cell apoptosis. Herein, irisin could increase apoptosis via stimulation of stimulated phosphorylation of AMPK and acetyl-CoA-carboxylase. EMT, epithelial–mesenchymal transition; HCC, hepatocellular carcinoma; AMPK, 5′ adenosine monophosphate-activated protein kinase.
Role of irisin in tissue invasion and metastasis
Metastasis is the common cause of mortality in most cancer patients. EMT is a unique phenotypic switch by which epithelial cells deprive their polarity and receive the invasive features of mesenchymal cells in the process of metastasis. 44 Furthermore, studies have exhibited that IL-6 can incite EMT in a few cancerous cells, for example, pancreatic, lung, hepatic, and CRC.45–48
A recent investigation reported that irisin suppressed the migration as well as invasion of osteosarcoma cells. 24 Moreover, irisin reversed IL-6-induced EMT in osteosarcoma cells followed by reduction of E-cadherin expression by IL-6. 24 In addition, irisin recovered the negative effect of IL-6 in a dose-dependent manner. The expression of N-cadherin, vimentin, fibronectin, matrix metallopeptidases (MMP)-2, MMP-7, and MMP-9 was upregulated with IL-6 treatment, and irisin effectively inhibited this effect in a dose-dependent manner (Figure 2). 24 Finally, the inhibitory role of irisin in IL-6 incited EMT had modulated through the STAT3/Snail pathway. To sum up, irisin reversed IL-6-initiated EMT of osteosarcoma cells through the STAT3/Snail signaling pathway. 24
Possible mechanism of irisin against EMT in cancerous cell lines. Irisin mediates its effects via the integrin receptor. Irisin significantly suppressed the proliferation, migration, and invasion of osteosarcoma cells. Moreover, irisin reversed the IL-6-induced EMT in osteosarcoma cells by regulating the expression of E-cadherin, N-cadherin, vimentin, fibronectin, MMP-2, MMP-7, and MMP-9. In addition, irisin suppressed the IL-6-activated phosphorylation of STAT3 and the expression of Snail in osteosarcoma cells. Migration and invasion of lung cancer cells are controlled by irisin via inhibition of the PI3K/AKT/Snail signaling pathway and EMT. IL-6, interleukin-6; PI3K, phosphatidylinositol 3-kinases; STAT3, signal transducer and activator of transcription 3; AKT, protein kinase B; EMT, epithelial–mesenchymal transition; MMP, matrix metallopeptidases.
A contemporary study revealed that upsurge trend of irisin immunoreactivity in tissues obtained from ovary, cervix, breast cancer, and endometrial hyperplasia indicated an important role of irisin during carcinogenesis. 16 Other studies demonstrated that irisin significantly reduced cell number, viability, and migration of malignant breast cancer cells (MDA-MB-231), 23 HCC (HepG2 and SMCC7721), 27 and pancreatic cancer cell (MIA PaCa-2 and Panc03.27). 29 Likewise, irisin reduced invasion of lung cancer cells (A549 and NCI-H446). 26 This study also demonstrated that irisin increased the expression of E-cadherin, and suppressed N-cadherin and vimentin, which is consistent with Kong’s study. 24 Finally, irisin potentially suppressed the migration and invasion of cancerous cells, regulated the EMT, inhibited MMPs. However, previous study has shown that irisin does not affect the cell proliferation and malignancy potential of obesity-related cancer cell lines. 25 This suggests that the action and role of irisin in cell proliferation and malignancy may be tissue and cell-specific. Furthermore, although the main assays performed in previous studies explored primary targets of cancer cell growth, they did not evaluate other aspects of malignant potential such as cell invasion and migration. In addition, in vitro irisin action in human and mouse cell lines may vary from those in vivo. Therefore, further studies are required to explore the role of irisin levels on obesity-related cancers in vivo in animals and subjects.
Multifunctional effects of irisin in cancer cells
A recent study has disseminated that an increased immunoreactivity of irisin in several cancerous tissues has a crucial role in cancer development. 16 Gannon et al. 23 have shown that irisin significantly increases the cytotoxic effect of doxorubicin (Dox) in malignant breast cancer cells without causing any side effects to nonmalignant cells. Shao et al. 26 reported that A549 and NCI-H446 cells treated with irisin can elevate the expression of E-cadherin, and reduce N-cadherin and vimentin, indicating that EMT may be inhibited by irisin treatment. Moreover, the expression of phosphorylated Akt diminished in lung cancer cells treated with various concentrations of irisin, indicating that irisin inhibits PI3K/Akt signaling pathway which is crucial for EMT. 26 Finally, these results suggested that the capability of invasion and migration in lung cancer cells may be regulated by irisin via inhibition of the PI3K/Akt/Snail signaling pathway and EMT. In summary, irisin significantly increased the sensitivity of anticancer drug without affecting noncancerous cells and inhibited EMT that may offer therapeutic opportunities for the treatment of cancer microenvironment.
Irisin concentration as a biomarker of tumor burden
Recently, significant improvements have been made in the diagnosis of a wide variety of cancers. Despite this advancement, a potential biomarker, which is capable of the diagnosis and prognosis of these cancers, is urgently required. It has been investigated that serum irisin closely interrelated with obesity, chronic kidney disease, and type 2 diabetes mellitus17,21,30–52. Moon and Mantzoros 25 revealed that the physiological (5–10 nmol/L) and pharmacological higher concentrations (50–100 nmol/L) of irisin practically had no effects on cell proliferation and malignancy potential of obesity-related cancer cell lines. Most recently, the study has demonstrated that the irisin concentration increased in the circulation by the progression of gastric cancer. 17 In addition, immunoreactivity of irisin has been increased significantly by both the ovarian endometriosis and mucinous carcinomas. 16 Based on this result, they concluded that the notable escalation of irisin immunoreactivity in several tissues procured from breast, ovary, and cervix carcinomas, and endometrial hyperplasia played a significant role during carcinogenesis. 16 The presumable relationship between irisin and breast cancer was suggested by proving distinguished serum irisin levels of breast cancer patients compared with those of control. 22 More clearly, the level of serum irisin in patients with breast cancer was considerably lower than in normal subjects; irisin levels could, therefore, be used as a diagnostic key marker in breast cancer. 22 Irisin also indirectly involved in heat production by transforming white adipose tissue to brown adipose tissue. However, the information is not available concerning how its expression alters in cancerous tissues. It has been reported that gastrointestinal cancer increases irisin expression. 12 The diagnostic significance of serum FNDC5/irisin levels in renal cancer patients was proved and suggested as a diagnostic cue for various types of cancer. 30 Furthermore, decreased serum irisin concentration in the patients with CRC may explain irisin could be a potential diagnostic biomarker for CRC patients. 32
Although previous studies showed that irisin is a promising biomarker for early diagnosis of various cancers, in some metabolic cancers it has been shown that the irisin levels increased; however, in other types of cancer, the irisin level decreased. Moreover, irisin levels vary based on factors such as muscle mass, age, and involvement in physical activities. These discrepancies must be addressed before irisin can be used as a biomarker by establishing a standard level of irisin in healthy individuals and cancer subjects.
Conclusion
In conclusion, irisin activates various anticancer mechanisms though different cancer pathways. We highlight the potential role of this myokine as a novel anticancer agent (Figure 3). Based on recent studies, irisin may be used as a therapeutic for the treatment of a wide variety of cancers by regulating lipid metabolism (Figure 3(a)), suppressing tumor-promoting inflammation (Figure 3(b)), increasing apoptosis (Figure 3(c)), and inhibiting metastasis (Figure 3(d)). In addition, irisin is a potential biomarker in several cancers including breast, renal, and CRC. Further studies are required to support the use of irisin as a standard biomarker and therapeutic to treat specific cancers.
Multiple proposed mechanisms through which irisin can exert anticancer effects. (a) Induces the phosphorylation of both HSL and perilipin via cAMP/PKA pathway, where perilipin serves as a gatekeeper and inhibits lipolysis that contains LD. The phosphorylation of HSL and perilipin induces converting stored triglycerides to glycerol and FFAs. Irisin-induced down-regulation of perilipin and up-regulation of HSL promote the lipolysis. (b) Inflammation can directly promote cancer growth and development by generating a wide array of inflammatory molecules, however, irisin can reduce inflammatory mediators (TNF-α and IL-6) possibly by inhibiting NF-kB. (c) Irisin induced apoptosis of malignant cells via activation of caspase-3 and caspase-7. (d) Irisin reduces migration, proliferation, and invasion of cancer cells by inhibiting the activation of PI3K/AKT pathway in cancer cells. Irisin controlled the migration and invasive ability of cancer cells by inhibiting the PI3K/AKT/Snail signaling pathway and EMT. cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; HSL, hormone-sensitive lipase; LD, lipid droplet; P, phosphorylation; FFA, free fatty acids; TG, triglycerides; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; PI3K, phosphatidylinositol 3-kinases; AKT, protein kinase B; EMT, epithelial–mesenchymal transition.
Footnotes
Acknowledgements
The authors thank members of the Hong’s lab for constructive and critical comments for this manuscript.
Author contributions
Y.H. contributed to conceptualization of the article; investigation was carried out by D.Md.S., Y.J., J.C., and J.Y.; D.Md.S. and Y.H. wrote the article; D.Md.S., Y.J., J.C., and J.Y. contributed to visualization; T.H.L. and Y.H. contributed to editing and supervision of the article.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a grant from Research year of Inje University in 2019–2020.
