2.1 Breast cancer
Breast cancer (BC) has become a common malignancy threatening women's health physically and mentally, and is prone to postoperative recurrence, with a high rate of malignant metastasis and an increasing incidence in younger adults [36]. Substantial evidence has revealed the effect of lifestyle and environmental factors on the development of BC, such as a high-fat diet, alcohol consumption, and lack of physical activity. The elimination of BC (primary prevention) may reduce morbidity and mortality. Secondary prevention, including diagnostic tests (e.g., mammography, ultrasonography, magnetic resonance imaging, molybdenum target mammography, breast self-examination, etc.), helps in the early detection of tumor-prone lesions [37, 38]. Although the postoperative 5-year survival rate of early BC can reach 80% [39], the postoperative distant recurrence and lung metastases adversely affect the overall survival rate for BC. Therefore, there is a need to further explore the signature oncogenes in BC cell growth and metastasis and to reveal their regulatory mechanisms in BC development.
One study found accelerated tumor growth and metastasis in mice after they were made to consume alcohol; in vitro, alcohol treatment significantly promoted BC cell proliferation and migration [40]. Alcohol chronic treatment induced a rise in the expression of reactive oxygen species (ROS) and ER stress activation protein p-eIF2a, BIP, and X-box binding protein 1 (XBP1)-s, and the reversal effect of 4-phenylbutyric acid (4-PBA) was observed on ethanol-induced chronic stress by pretreating E0771 cells, a murine BC cell line, with 4-PBA before ethanol treatment. Alcohol consumption is suggested to promote the malignant progression of BC cells through the induction of ER stress. ER stress inducer, tunicamycin, is a nucleotide antibiotic produced by actinomycetes. The mRNA and protein levels of ER stress-responsive genes (IRE1α and BIP) were upregulated in breast cancer cells [41]. The results showed that ER stress induced apoptosis in MDA-MB-231 by upregulating the expression of PERK, eIF2α, ATF4, CHOP, and caspase 4 that calpain could be a potential target for BC therapy [42]. A recent study [43] found that GRP78 was located intracellularly and not on the cell surface of the human BC cells MDA-MB-231 or it is secreted in the conditioned media. However, there is still a need to explore the signature oncogenes in BC cell growth and metastasis and to reveal their regulatory mechanisms in BC occurrence and development. Tripartite motif family protein (TRIM) 25 as a novel ER stress inducible protein that regulates the survival of BC cells by participating in ER stress induced apoptosis [44]. Recent research reports that combating multidrug resistance and metastasis of breast cancer by endoplasmic reticulum stress and cell-nucleus penetration enhanced immunochemotherapy [45]. There is a study revealed that GRP78 is a novel molecular link between glycolytic metabolism and ER stress during BC tumor metastasis [46]. P38-mediated induction of ER stress response is autophagy in human breast cancer cells. Activation of endoplasmic reticulum stress mediated pathway is an important cause of apoptosis of breast cancer cells. [47, 48].
Presently, studies on the effect of exercise on ER stress in BC are scarce. In a study of exercise combined with berberine administration, changes in the expression of downstream apoptosis-related proteins induced by the mitochondrial pathway, Fas-mediated death receptor pathway, and ER stress pathway were suggested to be the mechanism by which exercise co-operates with berberine to delay breast tumor growth [49]. Exercise as an adjunct is thought to protect against cancer development and metastasis by reducing hormonal stimulation in hormone-dependent cancers or by decreasing the permeability of the blood vessel wall to the invading metastatic cells. Exercise training increased circulating estrogen levels in the rat model of ovarian cancer, but the exact mechanism is not fully understood. The ER plays an important role in processes such as protein folding for hormone synthesis. Therefore, additional studies are necessary to address the potential protective vascular changes involved in exercise training-modulated anti-metastatic effects of ER stress in BC [50]. As ER stress induced apoptosis in tumor cells is gradually gaining momentum in research, revealing novel regulatory mechanisms between the ER stress related proteins and pathways and BC can provide new ideas and theoretical support for the early diagnosis and clinical treatment of BC in the future.
2.2 Ovarian cancer
Ovarian cancer (OvCa) is also one of the common gynecologic malignancies and can occur at any age. Owing to the lack of reliable screening tests and the ambiguous symptoms, ovarian malignancies are not easily detected in early-stage lesions and lack effective treatment in advanced cases; consequently, their morbidity and mortality rates rank the topmost in gynecologic malignancies [51]. Currently, OvCa clinical treatment is mainly based on chemotherapy, although chemotherapeutic drugs have disadvantages such as causing severe adverse reactions, unclear targeting, and prone to developing drug resistance [52]. Therefore, finding efficient and targeted treatments for OvCa is an urgent problem, and studying the molecular pathogenesis of OvCa is of utmost importance for the treatment of OvCa.
Studies have shown that ER stress may play an important role in the anticancer activity of proteasome inhibitors. ER stress-related genes are vital factors predicting the prognosis of OvCa, and possess great application potential in the clinic [53, 54]. Some scholars observed the effect of proteasome inhibitor MG132 on OvCa cell line SKOV3 in vitro, and found that MG132 induced ER stress in SKOV3 cells, and the CHOP gene-mediated ER stress apoptotic pathway played an important role in the anti-OvCa activity of MG132 [55]. There was a study demonstrated that ENTPD5 knockdown inhibited SOC cell proliferation, migration and restrained the activation of the GRP78/p-eIF-2α/CHOP pathway, which provides a potentially effective therapeutic target for the treatment of OvCa [56]. In contrast, when SKOV3 cells were treated with the inositol 1,4,5-triphosphate inhibitor, 2-aminoethyl diphenyl borate, in combination with cisplatin, cell survival was significantly increased, and the expression of ER stress related proteins GRP78, CHOP, and apoptotic protein caspase-3 was significantly decreased [57]. Studies have shown that OvCa may trigger the ER stress response, rapid activation of IRE1α/XBP1 and PERK/eIF2α/ATF4 axis, so that the dynamic imbalance between saturated and unsaturated fatty acids leads to ovarian cancer cell fate [58].
In recent years, the study of the role of exercise combined with herbal medicine therapy and dietary modification on OvCa has also become a hotspot. Increasing berberine concentration [59] was found to gradually enhance the expression of autophagy-associated protein and microtubule-associated protein 1 light chain 3 (LC3) and ubiquitin-binding protein p62 in SKOV3 cells, and significantly increase the expression of ER stress associated proteins, GRP78 and CHOP, and autophagy-associated proteins, beclin-1 and LC3. Exercise combined with berberine inhibited ER stress occurrence and autophagy in SKOV3 cells. In an investigation of the molecular mechanism of the induction of apoptosis in SKOV3 cells with the combination of the Chinese herbal medicine Chonglou saponin VII and cisplatin, increased expression of caspase 3 and apoptosis induction were observed. Meanwhile, the increased expression of XBP1 and ATF4 indirectly demonstrated that Chonglou saponin induced apoptosis in SKOV3 cells by activating the caspase pathway through ER stress [60]. At present, there are relatively few studies on the prevention and treatment of ovarian cancer through exercise regulating ER stress pathways. Exercise intervention can effectively alleviate fatigue and improve the quality of life of patients with OvCa, and long-term exercise training can regulate mitsugumin 53, a muscle-specific TRIM family protein, expression, which may reduce the risk of OvCa development [61]. Studying the regulatory effect and mechanism of exercise combined with herbal medicine, cognitive-behavioral therapy, and traditional Chinese medicine on OvCa is a potentially promising approach to OvCa treatment [62].
2.3 Cervical cancer
Cervical cancer is a malignant neoplasm occurring on the squamous and glandular epithelium of the uterine cervix. Studies have shown that high-risk human papillomavirus (HPV) infection is a major contributor to cervical lesions and cervical cancer [63]. HPV-16 and HPV-18, two high-risk HPV viral infections, are the most common types of infection in patients with cervical carcinoma [64]. Generally, the high incidence of in situ cancer is in the age range of 30-35 years and that of invasive cancer is 45-55 years, although, in recent years, its incidence is also showing a younger age trend. Fortunately, the widespread use of cervical cytology screening in recent decades has enabled early detection and treatment of cervical carcinoma and precancerous lesions, and the incidence and mortality rates of cervical cancer have generally decreased. Currently, cervical cancer treatment includes surgery, chemotherapy, and radiotherapy, although many patients eventually die from metastasis and recurrence of cervical carcinoma.
Studies have shown that [65] ER stress is closely associated with the occurrence and development of a variety of tumor diseases. The expression levels of ER stress related proteins can reflect different degrees of ER stress, and the processes of cellular reproduction and apoptosis are disrupted after ER stress occurrence. Since recent studies have found that HPV infection is closely associated with ER stress, studying the relationship between the expression levels of ER-related proteins and HPV infection has significant clinical implications. It was found that treatment of HeLa cells with curcumin led to increased expression of GRP78 and CHOP at the transcriptional and translational levels accompanied by inhibition of proliferation and occurrence of apoptosis. Quercetin induced apoptosis and ER stress by upregulating mRNA expression levels of eIF2α, ATF4, IRE1, XBP1, ATF6, PERK and CHOP in the HeLa cells. The up-regulating of mRNA expression level of GRP78 and activation of UPR are a molecular basis of quercetin-induced ER stress [66, 67]. Accordingly, they recently used RNA interference to silence Derlin-1 expression in overexpressed HPV16 E6 cells and found that decreased Derlin-1 expression was associated with no significant change in beclin-1 expression whereas p62 expression was increased. It is suggested that in the ER stress environment of HPV16 infection, Derlin-1 knockdown can affect the degradation of the p62 protein, leading to the blockage of the autophagic pathway. Derlin-1 is involved in the autophagic process during the autophagic-lysosome degradation phase and may serve as a communicating molecule between the ubiquitin-proteasome and autophagic-lysosomal pathways. These two protein degradation pathways may play a synergistic role in the ER stress process for maintaining cellular homeostasis, and this mechanism may be involved in HPV16-caused cervical cancer [68]. The expression rates of GRP78, c-Jun amino-terminal kinase, and enhancer-binding protein homologous protein were significantly higher in patients with high-risk HPV-16, HPV-18 infection, and cervical cancer than in low-risk HPV-6 infected and HPV-negative patients; additionally, the occurrence of HPV infection in cervical cancer cell lines was associated with the expression levels of ER stress related proteins [69]. The study showed that the FNDC3B was significantly upregulated in cervical cancer tissues. The immunofluorescence results obtained from the human protein atlas indicated that the FNDC3B protein is located in the ER and that it may play an oncogenic role in cancer development through ER stress, UPR, cell migration, and invasion [70]. The above study illustrates that the expression level of ER stress related proteins is associated with the occurrence and development of cervical cancer. ER stress activation might have a high value in the treatment and prognosis of cervical cancer and has good clinical prospects [71, 72].
The study has shown that the high expression of motor factor (AMF) in cervical cancer tissues is related to malignant biological characteristics and poor prognosis [73]. It is known that exercise can secrete motor factors. Our previous studies have shown that the motor factor irisin can inhibit apoptosis by regulating the IRE1α /XBP1 and IRE1α-TXNIP/ROS-NLRP3 pathways of ER stress [74, 75]. It is speculated that exercise secretion of motor factors may also play a beneficial role in the pathological process of cervical cancer by inhibiting ER stress pathways. The benefits of exercise in preventing cervical cancer in patients include improved physical function, fatigue, sleep quality, quality of life, anxiety, and depression, and may even reduce the risk of recurrence and prolong survival. However, to date, few studies have examined whether exercise exerts anticancer effects through modulation of the ER stress pathway, and further research is needed to determine the exact molecular mechanisms linking exercise to ER stress in the development of cervical carcinomas and to assess the potential of its associated pathways as novel therapeutic targets for the treatment of these diseases.
2.4 Polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is a common clinical disease of heterogeneous, multifactorial, genetic, and endocrine complex disorders in women of reproductive age, with a prevalence of 8–10% [76]. The main manifestations are amenorrhea or scanty menstruation, hyperandrogenism, polycystic ovarian, ovulatory dysfunction, etc., often accompanied by metabolic syndromes such as infertility, obesity, insulin resistance, and dyslipidemia. It is also a key factor in the development of pregnancy complications, diabetes, cardiovascular disease, and endometrial cancer [77, 78]. Despite the increasing incidence of PCOS, its etiology is not specifically documented.
Research has found that the relative expression of BIP mRNA and protein was significantly higher in the PCOS observation group than in the control group; similarly, the relative expression of CHOP mRNA and protein tended to be higher in the PCOS observation group than in the control group, although there was no significant difference [79]. The result several genes involved in UPRer and UPRmt were overexpressed in the GCs of PCOS-IR. IRE1, ATF4 and XBP1, that are activated by ER stress, were significantly overexpressed in PCOS-IR [80]. The expression of the ER stress markers GRP78, CHOP and XBP1s in the cumulus cells was higher in PCOS patients than in control patients, as were the levels of the UPR sensor proteins p-IRE1α, p-EIF2α and GRP78 [81]. ER stress triggers insulin resistance, and IR is the pathological basis of PCOS [82, 83]. Studies have shown that the reduction of granulosa cells in PCOS ovaries may be related to their apoptosis [84], although the exact molecular mechanism of granulosa cell-induced follicular atresia is not yet clear. Although research is still focused on the death ligand/receptor-dependent and mitochondria-dependent apoptotic pathways, the ER stress mediated apoptotic pathway in granulosa cells has also attracted increasing attention in recent years. Sigma-1 receptor is involved in diminished ovarian reserve possibly by influencing endoplasmic reticulum stress-mediated granulosa cells apoptosis [85]. ER stress mediated granulocyte apoptosis might contribute to the pathogenesis of PCOS. PCOS ovarian granulosa cells have multi-signaling molecule anomalies, such as the abnormal expression of insulin receptors α and β and their receptor substrate-1, decreased activity of insulin receptor, insulin receptor substrate 1 [86], and phosphatidylinositol 3-kinase in patients with PCOS, and decreased expression of glucose transporter protein 4, resulting in the occurrence of IR and decreased glucose uptake. ER stress is hypothesized to affect the apoptosis of granulosa cells by causing IR. Granulosa cells are protected by the upregulated expression of BIP within them. However, the CHOP-dependent apoptotic pathway is not yet activated, thus allowing the granulosa cells to persist, resulting in many antral follicles in patients with PCOS.
Previous studies have shown that aerobic exercise and curcumin improve follicular dysfunction in PCOS by inhibiting the IRE1α-XBP1 pathway of ER stress, and exercise-induced modulation of secreted myokine irisin improves follicular insufficiency in PCOS by inhibiting granulosa cell apoptosis through the IRE1α/thioredoxin interacting protein (TXNIP) axis of ER stress [74, 75]. However, exercise recommendations are vague and, therefore, difficult to implement owing to the lack of data on the type, intensity, or duration of exercise that produces benefits for women with PCOS. Well-designed trials are needed to guide the clinical management of PCOS in women of reproductive age. The focus should be on the role of exercise therapy in the prevention of PCOS to help develop individualized, appropriate types and intensities of exercise, and targeted exercise prescriptions to prevent the disease.
2.5 Endometriosis
Endometriosis (EMT) is a benign estrogen-dependent disease associated with pelvic pain and infertility, characterized by the ectopic distribution of endometrial tissue, mainly in the pelvic peritoneum and ovaries [87]. Currently, in patients with EMs, progestin resistance is an emerging feature of the disease, in addition to estrogen dependence. EMT is a chronic disease defined as a "benign cancer" requiring lifelong management, and despite its high prevalence, treatment outcomes have been unsatisfactory owing to the complexity of its pathogenesis and the diversity of its symptoms, making it a hot topic in gynecologic research [88]. Recent studies have shown that the occurrence of EMT is associated with abnormal apoptosis [89, 90], and ER stress mediated apoptosis is one of the important pathways.
The expression of phosphoinositide-kinase/protein kinase B (P13K/AKT) and GRP78 was shown to be significantly higher in ectopic endometrial lesion tissues than in normal endometrial tissues [91, 92]. High P13K/AKT pathway expression is one of the important mechanisms of ectopic endometrial mesenchymal cell migration. ER stress acts in cooperation with the P13K/AKT signaling pathway and is jointly involved in EMT pathogenesis [93]. Research has found that excessive reactive oxygen species induces senescence of endometriosis granular cells via arouse ER stress, which finally contributes to endometriosis-associated infertility, and melatonin may represent a novel adjuvant therapy strategy for endometriosis-associated infertility [94]. In addition, the mRNA and protein expression levels of GRP78, GRP94, caspase-12, and caspase-3 were also significantly lower in the proliferative and secretory ectopic endometrium of patients with EMT than in eutopic endometrium, this indicated that the ER stress mediated apoptotic pathway was more significantly downregulated in ectopic endometrium. Therapeutic induction of ER stress in endometriotic cells could promote apoptosis and contribute to the management of disease [95-97]. Therefore, novel therapeutic agents that focus on targeting ER stress induction may be an effective way to treat EMT.
Exercise plays a significant role in the treatment and prevention of EMT [98-100], and studies have shown that exercise is beneficial in reducing the intensity of pelvic pain, controlling stress levels, and improving psychological well-being in patients with EMT, thus improving the quality of life. Regular, low-intensity aerobic exercise is beneficial in reducing the intensity of the pain in endometriosis and the size of the uterus. Exercise is beneficial in reducing the risk of developing infertility in EMT by increasing the levels of associated endocrine factors and alpha-amylase. Exercise is also beneficial in reducing the risk of EMT by shrinking EMT lesions through fatty acid synthase, matrix metalloproteinase-9, changes in proliferating cell nuclear antigen protein expression, and lowering serum testosterone levels. ER stress mediated downregulation of apoptotic pathways may be one of the important mechanisms of EMT pathogenesis, which provides important clues for the in-depth study of the exact mechanism of EMT pathogenesis. Exercise modulates ER stress induced autophagy and apoptosis. In addition, exercise can inhibit inflammatory responses, oxidative stress, angiogenesis, and dysregulation of apoptosis. These are the underlying pathophysiological triggers that lead to EMT. Therefore, finding the proper prescription exercise, developing individualized exercise programs, and exploring targeted anti-over-ER stress, anti-inflammatory, antioxidant, anti-angiogenic, and apoptotic modulators are strategies and approaches to treat EMT disease.