Ovarian cancer (OC), as the most common and lethal gynecologic malignancies, is the fifth cause of cancer-related death in women globally [1, 2]. Due to the fact that OC is usually asymptomatic at early stages, most of the patients will ultimately progress to advance stages, resulting in a high rate of mortality [3, 4]. Despite recent advances, the lack of effective screening methods and therapeutic modalities are the major hurdles to improve prognoses for management of the disease and the main cause of 5-year survival rate of less than 40% [5]. Thus, exploring novel avenues to improve the status quo is urgently needed.
Obesity has been widely reported to be associated with the metabolic diseases including cancer [6–8]. Notably, obese people are usually at increased risk of developing cancers due to the higher levels of insulin and insulin-like growth factor-1, which may be responsible for certain tumors promotion [9]. Exercise is one of the several modifiable factors known to reduce the risk of developing human malignancies [10–13]. It has been also well documented that exercise has many benefits after diagnosis. There is increasingly mounting evidence that exercise relieve many of the common side effects contributed to the conventional cancer therapy among patients, resulting in a better overall quality of life [14–17]. Besides, a number of observational cohort studies support the view that cancer survivors who had a regular exercise suffered from a lower risk of relapse or cancer-related death after starting treatment regimens [18–20].
Recently, skeletal muscle is gaining special interest in terms of releasing various myokines which exert beneficial effects in metabolic disorders. Of these, irisin, a novel promising identified myokine releasing from skeletal muscle following exercise, is believed as a potential therapeutic in a variety of diseases [21, 22]. Previous studies have documented the positive association between irisin and body energy expenditure as well as insulin sensitivity [23]. Additionally, irisin has been verified to have a pivotal role in smooth muscle cell phenotype modulation by regulating endothelial cell proliferation, apoptosis and migration [24]. Due to the strong metabolic effects of irisin on several tissue types, it is questionable whether irisin has the ability to modulate malignant features of cells and tissues similar to other myokines [25]. In the past decade, the relationship between irisin and different cancers have been the focus of many studies. Represented data from a recent study found a lower level of serum irisin in patients with breast cancer, while other studies indicated that irisin was significantly increased in gastrointestinal cancer tissues [26–28]. Moreover, a number of studies have detected increased irisin immunoreactivity in ovarian, cervix and breast cancer tissues as well as endometrial hyperplasias [29].
In the context of cancer metabolism, reprogramming of glucose metabolism is a pervasive microenvironmental event in tumorigenesis. To this end, cancer cells preferentially switch from oxidative phosphorylation (OXPHOS) to glycolysis, even under normal oxygen concentration. This particular metabolic profile –defined as Warburg effect- is a key hallmark of many solid tumors including OC [30].
Growing evidence demonstrated that many signal molecules including tumor suppressor genes and oncogenes play substantial roles in conferring metabolic advantages and adaptation to the tumorigenic microenvironment [30]. Of these documented genes, the hypoxia-inducible factor-1α (HIF-1α) is a transcription factor regulating many pivotal pathways in cancerous cells [31].
Although the importance of HIF-1α in the induction of the Warburg effect is largely highlighted, the involvement and influences of other factors should not be underestimated. A number of studies notably suggested that crosstalk between HIF-1α and oncogenic c-Myc lead to increased uptake of glucose and its conversion to lactate which subsequently modulate the cancer cell’s microenvironment through regulation of common downstream target genes, such as pyruvate dehydrogenase kinase 1(PDK1) and lactate dehydrogenase A (LDHA) [32]. It is also noticeable that angiogenesis is necessary for tumor growth and metastasis .HIF-1α also upregulates the expression of the angiogenic growth factors such as vascular endothelial growth factor (VEGF), which in turn stimulates neovascularization a fundamental process for tumor progression [33].
Considering the above mentioned points, we intended to evaluate the effect of irisin as a promising myokine on tumorigenic features of ovarian cancer cells and to regulate genes correlated with aerobic metabolism.