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Exercise-Induced Irisin, the Fat Browning Myokine, as a Potential Anticancer Agent.

1. Introduction

Obesity, along with the metabolic diseases it causes, has become an increasingly growing problem that has devastating economic, health, and societal effects. From insulin resistance and hyperlipidemia to cardiovascular diseases and cancer, obesity has been associated with many of the leading causes of death worldwide [1, 2]. Despite its prevalence, excess weight can be greatly reduced by following a healthy diet and a good exercise routine [1]. In fact, exercise is known to exert beneficial effects on all body systems. Studies have repeatedly proven the positive effects exercise has on the cardiovascular, respiratory, and skeletomuscular systems [3]. Exercise induces these changes by the release of hormones and myokines from the skeletomuscular system in the body [4]. Some of these myokines include BDNF, FGF-21, IL-15, and irisin [4, 5]. Indeed, one of these myokines, irisin, which was only recently discovered, has been shown to have numerous benefits not only in fighting metabolic diseases but also in combating cancer [4]. Recent reviews in the literature link irisin and exercise, concluding that irisin increases after exercise, however only transiently [6]; irisin, obesity, and metabolic diseases have also been linked [7], but no review summarizes the studies that show the effect of irisin on cancer or cancer biology. An investigation into the available literature shows that irisin has direct effects on different types of cancers. However, some controversies remain on the exact benefits of irisin on cancer with some studies showing no or even a negative effect of irisin on cancer. This review summarizes these 2 differing viewpoints and synthesizes them to form a clearer picture of irisin's effects on cancer and questions if irisin is the missing link between obesity, exercise, and cancer.

2. Methods

The articles listed in Section 3.4 were selected based on relevancy from PubMed and Google Scholar databases. Initial results yielded 56 articles on PubMed and 9280 articles on Google Scholar where "Irisin" and "Cancer" were used as keywords. After reading all the abstracts to refine the selection, only 17 articles were found to directly link irisin with cancer as these articles mentioned the direct effect of irisin on cancer cell lines in vitro and the effects of serum irisin in cancer patients in vivo.

3. Results

From the 17 articles selected and reviewed for the "irisin and cancer,"

(i) Thirteen articles (Table 1) favoured irisin as a myokine with a role in carcinogenesis or cancer therapeutics (7 studies were conducted in vitro, and 6 studies were performed in vivo)

(ii) Four articles considered that irisin has no or adverse effect on cancer progression

3.1. Irisin. Irisin is released through the cleavage of FNDC5, a polypeptide protein containing 212 amino acids. This protein is cleaved at the N-terminal releasing irisin, originally named after the Greek goddess Iris, into the blood [21]. This cleavage is initiated by muscle contraction through an unknown proteasome [21]. Irisin levels are increased after acute exercise and bind to an unidentified receptor on the adipose tissue, which leads to significant weight loss and decrease in total body energy [21].

Recent studies of its function have determined that its beneficial effects derive from its ability of browning white adipose cells. The molecular cascade that ties irisin and the browning of white fat is the following: first, exercise increases the expression of PGC-1[alpha] or peroxisome proliferator-activated receptor (PPAR-[gamma]) coactivator. This in turn increases the expression of FNDC5, which, as stated before, releases irisin. Irisin then increases the mRNA expression of UCP1, a transmembrane protein that decreases the proton gradient generated by oxidative phosphorylation [21].

3.2. Irisin and Exercise. Since irisin was linked with muscle contraction, studies were conducted to measure irisin levels after exercise. Several studies were conducted to measure the levels of irisin after exercise especially in overweight individuals. The selected articles of this section are based on recent studies conducted between 2014 and 2017 showing the relationship of irisin and exercise; the studies were performed on individuals of various body types and on mice. A murine study concluded that a significant increase in irisin levels and UCP1, which leads to increased thermogenesis in the white adipose tissue, was seen after rats were subjected to resistance exercise [22]. Another study conducted on humans indicated a significant increase in irisin levels among obese youth after exercise. However, this increase was observed directly after aerobic exercise while no change was observed after resistance exercise [23]. Other studies linked irisin levels with BMI, obesity, and leptin, where obese children who had undergone a physical activity program showed a significant increase in levels of irisin and leptin. This suggests that irisin could possibly link the skeletomuscular system with the adipose tissue [24]. A murine study conducted on high-fat diet-induced obese mice concluded that mice exposed to intravenous irisin gained similar benefits as those who had exercised. This study also showed that these two groups had improved insulin resistance and levels of reproductive hormones and improved ovarian follicle health [25]. Irisin was also found to induce muscular hypertrophy when injected into mice after activation of satellite cells and increase protein synthesis [26]. Lastly, in a study conducted on healthy human subjects, irisin and lactate levels were positively correlated and both increased with higher exercise workload, confirming the researchers' hypothesis that irisin is tied to muscle energy demands [27]. This correlation could suggest that the increased strain on the muscles and low ATP may signal irisin release. Interestingly, individuals who were able to reach a higher V[O.sub.2max] and thus work at a higher exercise workload produced higher levels of irisin after exercise [27]. These studies show a clear pattern between irisin and exercise where exercise induced a significant increase in irisin secretion.

3.3. Irisin and Obesity. Irisin, originating from the white adipose tissue in mice, is thought to form around 30% of total body irisin, while in humans, muscle FNDC5/irisin expression is 100-200 times higher than in the white adipose tissue [28]. Another interspecies difference irisin shows is that its browning effects in humans may be different than those in rodents. Indeed, irisin decreases browning-related genes in human preadipocytes but increases said genes in mature human adipocytes [6, 21].

Since irisin increases energy expenditure through its aforementioned effects on UCP1, it is expected that it should reduce body weight. Hence, it is paradoxical that obese individuals show increased irisin levels as compared to normal weight individuals. In fact, anorexic patients show as much as 30% reduced irisin levels compared to morbidly obese individuals. It is surmised then that while increased fat deposits increase the production of irisin, irisin itself can no longer exert its effects in a meaningful manner; thus, obese individuals may have irisin resistance, a condition not too different from leptin resistance, where increased leptin levels fail to enact their beneficial effects. In turn, leptin is also positively correlated with obesity and irisin itself [29]. Many studies revealed a link between irisin and obesity due to its secretion by the adipose tissue and have found a positive correlation between BMI and irisin [7].

3.4. Irisin and Cancer. A large body of evidence has linked obesity to cancer because obesity leads to an increase in inflammatory markers (IL-6 and TNF-[alpha]) [30], insulin resistance [31], and adipokine secretions [32], all of which favor tumor survival and proliferation [33], while exercise has also shown to have potential anti-inflammatory effects by reducing of TNF-[alpha] expression [34]. Thus, since irisin is linked to obesity, it follows to hypothesize that irisin could be associated with cancer as well (Figure 1). Tying together obesity, irisin, and cancer, exercise, which helps combat obesity, also increases irisin levels [23]. Exercise-induced irisin could be used as a determinant of the metabolic response to exercise in obese individuals to track any decrease in cancer risk linked to obesity [35]. To study irisin's effects on cancer, a study was conducted on human nonmalignant breast epithelial cells (MCF-10a), malignant breast epithelial cells (MCF-7), and malignant aggressive breast epithelial cells (MDA-MB-231). Upon exposure to irisin, the malignant breast tumor cell number significantly decreased as a result of increased caspase-3/7 activity and suppression of NF-[kappa]B activity. This shows that irisin could possibly reverse the cancer hallmark of resisting cell death [36, 37] by promoting caspase 3 activity and thus apoptosis. A significant decrease in cell migration compared to the control was also noted. Moreover, the malignant breast cells were exposed to doxorubicin, a chemotherapy agent, and irisin. When exposed to irisin, these cells showed a significant increase in doxorubicin sensitivity and a significant decrease in malignant cell viability and number. In fact, this increased doxorubicin sensitivity meant that less doses of doxorubicin were even more effective at producing the desired chemotherapy effects. Thus, irisin could play an important role in cancer therapy [10]. Another study on irisin and breast cancer showed that there was a negative correlation between serum levels of irisin and spinal metastasis of breast cancer. Irisin was found to have a protective effect on the bone, and these favorable bone qualities protected from metastasis of breast cancer [19]. This shows that irisin's effects also could reduce the metastatic and invasive hallmarks of cancer [36].

Yet another study suggested that increased levels of serum irisin reduced the risk of breast cancer development by 90%, and patients that had developed breast cancer had a significantly lower irisin serum levels than healthy individuals [9].

Aiming to uncover irisin's relation to other types of cancers, two studies conducted on lung cancer cells concluded that an increase in irisin levels led to a decrease in lung cancer cell proliferation, viability, and invasiveness by affecting the epithelial-mesenchymal transition (EMT), significantly decreasing the EMT markers N-cadherin and vimentin and increasing the expression of Thcadherin. This inhibition in EMT was related to the inhibition of the Snail pathway which is mediated by the PI3K/Akt pathway [8]. Irisin's effect on the PI3K pathway may also suggest an inhibitive role and a reason for the reduction in cancer cell proliferation. The second study conducted on osteocarcinoma cells also confirmed these findings and deduced that irisin was able to reverse IL-6-induced EMT by inhibition of the STAT3 pathway [18]. Another recent study conducted on pancreatic cancer cell lines also showed irisin's ability to inhibit EMT, viability, and proliferation of these cells by activation of the AMPK pathway. Irisin inhibits pancreatic cancer cell growth via the AMPK-mTOR pathway [20]. This ability of irisin to target the AMPK pathway may also suggest its role in reducing proliferation and altering cancer energy metabolism [37, 38]. A study conducted on prostate cancer cells subjected to different concentrations of irisin showed reduced prostate cancer cell viability [13]. Furthermore, a study on renal cell cancer suggested that irisin can be used as a biomarker for renal cancer diagnosis as irisin levels were significantly increased in patients with renal tumors; irisin too had higher specificity and sensitivity than other investigated biomarkers [11]. In a recent study conducted, patients with colorectal cancer showed low serum irisin levels compared to healthy individuals while individuals with high levels of irisin showed a 78% reduced risk of developing colorectal cancer (CRC). These findings could show that irisin could have protective qualities against development of CRC [14].

3.5. Controversies. Despite what appears to be a positive correlation between irisin and cancer, two studies conducted on hepatocellular carcinomas have suggested that irisin stimulated the proliferation and invasion of hepatocellular carcinoma tumors via activation of the PI3K/AKT pathway. This study also showed a reduction in doxorubicin cytotoxicity in the presence of irisin [16].The second study showed a significant increase in expression of hepatic irisin mRNA in individuals with hepatic carcinoma [12].

Furthermore, a murine study conducted to assess the relationship between cachectic factors and irisin in gastric cancer showed no significant difference in the expression of FNDC5 in gastric cancer tissues. However, FNDC5 expression was increased in the subcutaneous adipose tissue, and an overall increase in irisin serum levels was noted. Nevertheless, these increased serum irisin levels seen in this study failed to increase UCP1 expression in the white fat tissue, while increased irisin levels due to exercise do increase UCP1 expression [17]. Therefore, this shows that the increased irisin levels due to exercise operate differently than those seen in gastric cancer and possibly other types of cancer.

Moreover, a study conducted on several cancer cell lines where adhesion activity and colony numbers were measured failed to show any effects of irisin on the proliferation and malignant potential of these cell lines [15]. Indeed, these studies showed that perhaps the beneficial effects of irisin are cell- or tissue-specific and may not be observable in all cancer types.

4. Discussion

Exercise has shown its positive influence in numerous chronic diseases, especially obesity, but the direct path that causes these positive changes remained elusive [39]. Exercise has also shown its effect on several hallmarks of cancer [38]. No study has yet revealed the exact type and duration of exercise that should be performed to decrease cancer risk. In our present review, we shed the light on irisin as an exercise-secreted myokine, and we summarize the studies that show the effect of irisin on some of the hallmarks of cancer. Indeed, the studies conducted showed that cancer cells exposed to irisin presented an increase caspase activity, a suppression of NF-[kappa]B activity, thus a reduction of the "resisting cell death" hallmark [36]. Other studies showed a role of irisin in suppressing other hallmarks of cancer such as "sustaining proliferative signaling" [36] by targeting the PI3K/Akt pathway [16] or "evading growth suppressors" [36] via targeting the AMPK-mTOR pathway [20] or "activating invasion and metastasis" [36] by decreasing cell migration and inhibiting the epithelial-mesenchymal transition [18]. Irisin belongs indeed to the emerging group of myokines that are hypothesized to reduce cancer risk by lowering the basal systemic levels of cancer risk factors such as proinflammatory cytokines and adipokines [37, 40].

5. Conclusion

Further mechanistic studies are necessary to determine how irisin induced fat browning and obesity reduction may reduce carcinogenesis or cancer risk. As for the potential role of irisin in cancer therapeutics, more studies should be performed in order to determine the mode of administration of irisin for each cancer type. Nevertheless, obesity has become a worldwide epidemic disease, and many diseases related to obesity also present a steady rising, including insulin resistance, metabolic syndrome, type II diabetes, hypertension, chronic kidney disease, cardiovascular disease, heart failure, and cancer. Therefore, exercise-induced irisin deserves a closer inspection to further understand its direct role in reducing obesity and to elucidate its part in cancer prevention and therapeutics.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

https://doi.org/10.1155/2019/6561726

Acknowledgments

This work was supported by a grant from the National Council for Scientific Research (CNRS)-Lebanon (grant 739/S).

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George-Emmanuel Maalouf and Diala El Khoury [ID]

Department of Sciences, Notre Dame University-Louaize, P.O. Box 72, Zouk Mikael, Lebanon

Correspondence should be addressed to Diala El Khoury; delkhoury@ndu.edu.lb

Received 15 November 2018; Accepted 14 March 2019; Published 1 April 2019

Academic Editor: Mario Musella

Caption: Figure 1: Diagram representing the putative relationship between exercise-induced release of irisin, obesity, and cancer. A possible anti-inflammatory role of irisin could also be inferred by its ability of browning fat cells, reducing obesity and thus reducing the inflammatory microenvironment. Irisin may also have a direct effect on other cancer hallmarks.
Table 1: Studies that show the promising effects of irisin on
different types of cancer.

Subject/animal/     Tumor/cell           Treatment/groups
culture             model

Lung cancer cells   A549 and NCI-H446    Treated with 0, 10, 20,
                    lung cancer cells    or 50 nM irisin,
                                         respectively, for
                                         different time periods
                                         (0, 24, and 48 h)

Female patients     --                   Two groups: 101
with invasive                            females with invasive
ductal breast                            ductal breast cancer
cancer and                               and 51 healthy
healthy women                            females

Breast cancer       MDA-MB-231 cells     MDA-MB-231 and
cells               and MCF-10a cells    MCF-10a cells were
                                         treated with human
                                         recombinant
                                         nonmodified irisin
                                         (INM) or human
                                         recombinant
                                         modified and active
                                         (glycosylated) irisin
                                         (IM)

Patients with       --                   Two groups: 23
renal cell cancer                        patients with renal
and healthy                              tumor and 25 healthy
subjects                                 individuals
                                         Two groups: 18
                                         patients with HCV-
                                         related HCC
                                         undergoing liver
                                         transplantation and
                                         18 deceased liver
                                         donors

Patients            --
undergoing liver
transplantation
and deceased
donors

Prostate cancer     DU-145 and PC3       Treated with 0.1,1,10,
cells                                    and 100 nM irisin

Patients with       --                   76 CRC patients and
colon and rectal                         40 healthy controls
cancer

Endometrial,        KLE and RL95-2,      Cells were treated
colon, thyroid,     HT29 and MCA38,      with irisin for a
and esophageal      SW579 and BHP7,      period between 24
cell lines          and OE13 and OE33    and 36 hours

20 patients with    HepG2 and            Cells were treated
hepatocellular      SMCC7721             with glycosylated and
carcinoma and                            nonmodified irisin
hepatocellular                           for 24 h.
carcinoma cells.

60 BALB/c mice      --                   12 mice as controls
                                         and 48 mice receiving
                                         carcinogenic MNU

Osteosarcoma        U2OS and MG-63       Osteosarcoma cells
cells               osteosarcoma cells   were treated with
                                         different doses of
                                         irisin (0, 25, 50, 100,
                                         and 200ng/ml) for
                                         different times (12,24,
                                         and 48 h) and were
                                         also treated with and
                                         without IL-6

148 female          --                   --
patients with
breast cancer

Pancreatic cancer   MIA PaCa-2 and       Cells were treated
cell lines          Panc03.27            with different
                    Panc03.27            concentrations (0, 10,
                                         and 100 nM) of E-irisin
                                         and P-irisin for
                                         2 weeks

Subject/animal/     Main results
culture

Lung cancer cells   (i) Over a range of
                    concentrations
                    (20-50 nM), significantly
                    irisin inhibits A549 cells
                    proliferation as detected
                    by MTT assay
                    (ii) Irisin may alter the
                    expression of EMT
                    markers in a
                    concentration-
                    dependent manner and
                    indicate that the
                    inhibitory effect of irisin
                    on lung cancer cells
                    invasion and migration
                    may be associated with
                    EMT.

Female patients     (i) Irisin discriminates
with invasive       between patients and
ductal breast       healthy individuals at an
cancer and          optimal value of 3.21
healthy women       [micro]g/ml
                    (ii) Irisin levels were
                    positively associated with
                    tumor stage
                    (iii) No significant
                    association between
                    irisin and tumor grade,
                    and irisin and CEA, and
                    CA15-3 and Her2/neu

Breast cancer       (i) INM did not affect
cells               nonmalignant MCF-10a
                    cell viability, but IM
                    decreased it
                    (ii) Malignant MDA-
                    MB-231 cell viability was
                    significantly reduced by
                    INM, but not IM
                    (iii) INM decreased cell
                    number while IM did not
                    (iv) Caspase-3/7 activity
                    was significantly elevated
                    when cells were treated
                    with INM but not when
                    treated with IM
                    (v) IM enhanced Dox
                    killing at 1.0 [micro]M, while
                    INM enhanced it at all
                    tested concentrations

Patients with       (i) Significantly elevated
renal cell cancer   FNDC5/irisin levels and
and healthy         CEA in patients with
subjects            renal tumor
                    (ii) FNDC5 levels
                    showed higher sensitivity
                    and specificity indexes
                    when compared to CEA

Patients            (i) Irisin mRNA
undergoing liver    expression was
transplantation     significantly higher in the
and deceased        liver of HCC patients
donors              than in liver donors
                    (ii) SCD-1, NOTCH1,
                    IL-6, and TNF-[alpha] were
                    significantly higher in
                    HCC patients than in
                    donors
                    (iii) Irisin mRNA
                    correlated with the
                    plasma lipid profile
                    (triglycerides), DNL
                    index, and PUFA/SFA
                    ratios

Prostate cancer     (i) Irisin reduced
cells               proliferation and cell
                    viability of the DU-145
                    and PC3 cells when
                    treated with 10 and
                    100 nM of irisin,
                    respectively

Patients with       (i) Patients with CRC
colon and rectal    have significantly
cancer              reduced levels of irisin
                    (ii) High serum irisin
                    levels had a 78% reduced
                    risk of developing CRC.

Endometrial,        (i) No change in cell
colon, thyroid,     adhesion or colony
and esophageal      number
cell lines          (ii) No effect on cell
                    proliferation

20 patients with    (i) HepG2 and
hepatocellular      SMCC7721 viability and
carcinoma and       proliferation increased
hepatocellular      (ii) Doxorubicin
carcinoma cells.    cytotoxicity was reduced

60 BALB/c mice      (i) No FNDC5/irisin
                    expression was detected
                    in cancerous stomach
                    tissue
                    (ii) Significant increase in
                    FNDC5/irisin expression
                    in subcutaneous adipose
                    tissue after development
                    of cancer

Osteosarcoma        (i) Irisin significantly
cells               suppressed osteosarcoma
                    cell viability after 24 h
                    (ii) Irisin significantly
                    inhibited osteosarcoma
                    cell proliferation after
                    48 h
                    (iii) Irisin reversed the
                    effect of IL-6 and
                    suppressed EMT
                    transition
                    (iv) Irisin downregulated
                    STAT3 phosphorylation
                    (v) Irisin inhibits Snail
                    expression via STAT3
                    pathway

148 female          (i) Patients with spinal
patients with       metastasis had
breast cancer       significantly lower levels
                    of serum irisin
                    (ii) High serum irisin
                    levels reduced the risk of
                    spinal metastasis by 20%

Pancreatic cancer   (i) Reduced PaCa-2 and
cell lines          Panc03.27 viability
                    (ii) Reduction in mobility
                    and invasiveness
                    (iii) Upgregulation of E-
                    cadherin expression
                    (iv) Increase in
                    phosphorylation of
                    AMPK

Subject/animal/     Authors' main               Reference
culture             conclusions

Lung cancer cells   (i) Inhibition of           Shao et al. [8]
                    proliferation,
                    migration, and
                    invasion of
                    osteosarcoma cells
                    (ii) Suppression of IL-
                    6-induced EMT in
                    osteosarcoma cells
                    (ii) targeting the
                    STAT3/Snail
                    signaling pathway

Female patients     (i) Irisin may serve as     Provatopoulou
with invasive       a novel biomarker for       et al. [9]
ductal breast       breast cancer
cancer and          diagnosis
healthy women       (ii) An understanding
                    of irisin's role in
                    health, and disease is
                    lacking

Breast cancer       (i) Irisin is a potential   Gannon et al.
cells               therapeutic agent for       [10]
                    cancer
                    (ii) Irisin may have an
                    anti-inflammatory
                    effect, counteracting
                    the effects of TNF-a
                    (iii) Irisin affects
                    malignant cells
                    without affecting
                    nonmalignant cells

Patients with       (i) Irisin may be a         Altay et al. [11]
renal cell cancer   useful marker in the
and healthy         diagnosis of cancer
subjects

Patients            (i) Irisin levels           Gaggini et al.
undergoing liver    increase in                 [12]
transplantation     hepatocellular
and deceased        carcinoma as a
donors              compensatory
                    mechanism to limit
                    cancer-induced
                    lipogenesis.
                    (ii) No correlation
                    between hepatic irisin
                    levels and plasma
                    irisin levels, possibly
                    due to plasma irisin
                    levels depending on
                    the sum total of the
                    adipose tissue and
                    skeletal muscle

Prostate cancer     Irisin has a cytotoxic      Tekin et al. [13]
cells               effect on prostate
                    cancer cells on
                    both [+ or -] androgen
                    receptors in a
                    dose-dependent manner

Patients with       (i) Irisin could act as a   Zhu et al. [14]
colon and rectal    potential serum
cancer              diagnostic biomarker
                    for CRC
                    (ii) Irisin could be a
                    protective factor in
                    CRC development

Endometrial,        (i) Irisin did not have     Moon and
colon, thyroid,     an effect of cell           Mantzoros [15]
and esophageal      proliferation or
cell lines          malignant potential
                    of human and mouse
                    obesity-related cancer
                    cell lines

20 patients with    (i) Irisin regulates        Shi et al. [16]
hepatocellular      liver cancer cell
carcinoma and       proliferation
hepatocellular      (ii) Irisin significantly
carcinoma cells.    increases the
                    activation of the
                    PI3K/AKT pathway
                    (iii) Irisin reduces
                    doxorubicin
                    sensitivity

60 BALB/c mice      (i) Gastric tumors          Altay et al. [17]
                    stimulated the release
                    of FNDC5 leading to
                    weight loss

Osteosarcoma        (i) Irisin suppressed       Kong et.al. [18]
cells               metastasis by the
                    inhibition of EMT via
                    the STAT3/Snail
                    pathway
                    (ii) Irisin suppressed
                    the migration and
                    invasion of
                    osteosarcoma cells
                    (iii) Irisin reversed
                    the EMT induced by
                    IL-6

148 female          (i) Irisin has              Zhang et al.
patients with       protective qualities        [19]
breast cancer       against the
                    development of spinal
                    metastasis
                    (ii) Irisin can be used
                    as a predictive marker
                    for bone metastasis

Pancreatic cancer   (i) Irisin suppressed       Liu et al. [20]
cell lines          invasion and
                    migration of
                    pancreatic cancer
                    cells by inhibiting
                    EMT
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Author:Maalouf, George-Emmanuel; Khoury, Diala El
Publication:Journal of Obesity
Date:Apr 30, 2019
Words:5142
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