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Mitogen-Activated Protein Kinase (MAPK) and Obesity-Related Cancer

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Mitogen-Activated Protein Kinase (MAPK) and Obesity-Related Cancer International Journal of Molecular Sciences Review Mitogen-Activated Protein Kinase (MAPK) and Obesity-Related Cancer Fionán Donohoe 1 , Michael Wilkinson 1, Eva Baxter 2 and Donal J. Brennan 1,3,* 1 Ireland East Hospital Gynaeoncology Group, UCD School of Medicine, Mater Misericordiae University, D07R2WY Dublin 7, Ireland; fi[email protected] (F.D.); [email protected] (M.W.) 2 Queensland Centre for Gynaecological Cancer Research, The University of Queensland, Brisbane QLD 4029, Australia; [email protected] 3 Systems Biology Ireland, UCD School of Medicine, Belfield, D04V1W8 Dublin 4, Ireland * Correspondence: [email protected]; Tel.: +353-1-7164567 Received: 31 December 2019; Accepted: 12 February 2020; Published: 13 February 2020 Abstract: Obesity is a major public health concern worldwide. The increased risk of certain types of cancer is now an established deleterious consequence of obesity, although the molecular mechanisms of this are not completely understood. In this review, we aim to explore the links between MAPK signalling and obesity-related cancer. We focus mostly on p38 and JNK MAPK, as the role of ERK remains unclear. These links are seen through the implication of MAPK in obesity-related immune paralysis as well as through effects on the endoplasmic reticulum stress response and activation of aromatase. By way of example, we highlight areas of interest and possibilities for future research in endometrioid endometrial cancer and hepatocellular carcinoma associated with non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and MAPK. Keywords: obesity; MAPK; cancer; endometrial cancer; hepatocellular cancer 1. Introduction Obesity is a major public health concern that develops as a result of chronic caloric excess. The excess energy is stored as lipid in adipose tissue and may accumulate in other metabolic organs (such as the liver) and skeletal muscle. Increased lipid accumulation significantly alters the normal metabolic milieu and creates an environment that chronically transmits a signal of nutrient excess to the cell, with multiple consequences, many of which are poorly understood. Global obesity rates have been increasing dramatically over the last number of years, with rates now almost triple what they were in 1975. According to the World Health Organisation, there were 1.9 billion overweight adults worldwide in 2016, with 650 million of those classified as obese, representing 13% of the world’s population. Once considered a problem confined to the developed world, obesity rates are also increasing in middle- and low-income countries with a fifty percent increase in the numbers of overweight children in Africa since the year 2000 [1,2]. The effect of obesity on cardiovascular disease and diabetes is well established, however the association between obesity and increased risk of certain types of cancer is a relatively new observation and the underlying mechanisms have not been fully elucidated. Improved understanding of the molecular interactions between obesity and cancer is important if any future public health interventions are to be successful in reducing population obesity levels and the associated cancer risk. MAPK pathways are signalling modules that transduce extracellular and intracellular signals to regulatory networks within the cell via the phosphorylation of key protein targets. Each cascade is activated by extracellular signals which lead to the activation of the MAPK through successive activations of MAPK kinase kinase (MAPKKK) and MAPK kinase (MAPKK). There are three main Int. J. Mol. Sci. 2020, 21, 1241; doi:10.3390/ijms21041241 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 1241 2 of 19 families of MAPK—the extracellular signal regulated kinases (ERKs), the Jun amino terminal kinases (JNKs) and the stress activated protein kinases (p38/SAPKs). The ERKs respond primarily to growth factors and mitogens to induce cell growth and differentiation, while the JNKs respond primarily to stress such as ionising radiation and oxidative stress and are involved in apoptosis, cytokine production, inflammation and metabolism. Similarly, the p38 MAPKs are strongly activated by cytokines and cellular stress. The activation of the p38 MAPK pathway contributes to inflammation, apoptosis, cell differentiation and cell cycle regulation [3]. The involvement of the ERK pathway in obesity-related cancer is poorly understood at present and as the JNKs and p38 are thought to be the more important groups influencing obesity, they will be the focus of this review. In this review, we discuss the relationship between obesity and cancer and the mechanisms underlying obesity-related carcinogenesis, with a focus on mitogen-activated protein kinase (MAPK) signalling. To do this, we have chosen endometrial cancer as a case study, for the following reasons, (a) the epidemiological association between obesity and endometrial cancer is irrefutable, and (b) weight loss reduces endometrial cancer. We also discuss the role of obesity and MAPK in hepatic steatosis. 2. Obesity-Related Cancers—Epidemiological Perspective Epidemiological evidence linking obesity to cancer development is consistent and compelling for cancer of the oesophagus (adenocarcinoma), kidney, breast (postmenopausal), colon, rectum, endometrium, liver, thyroid, gallbladder, ovary and pancreas [2,4]; however, the relative risks differ between cancer types. The most compelling relationship with obesity has been demonstrated in endometrioid endometrial cancer, adenocarcinoma of the oesophagus and cholangiocarcinoma. 3. Obesity and Metabolic Dysfunction as Cancer Risk Factors Overall there is a modest but important increase in the relative risk of developing any cancer in the order of 1.06–1.62 for each increment of body mass index BMI of 5 kg/m2 [4]. In 2012, it was estimated that 3.6% of all new adult cancers over 30 years of age were attributable to high BMI, with the impact greater in countries where obesity was more prevalent, and a greater burden of risk for women than for men [5]. In those with a BMI greater than 40 kg/m2, the risk of death attributable to cancer is higher than those with a normal BMI, although most of the observed decrease in life expectancy in this group is attributable to cardiovascular events [6], again highlighting the importance of public health interventions in this population. Obviously, there are multiple confounding factors, such as levels of physical activity, energy balance and metabolism in obesity-related carcinogenesis, and many have not been fully explored from an epidemiological perspective [7]. Of these confounders, metabolic dysfunction may be the most important confounder. The concept of healthy obese patients, i.e., those with no evidence of diabetes, hypertension or other co-morbidities, has gained a lot of traction in recent years. As a result, there has been an increased interest in the role of metabolic aberrations in cancer risk and outcome. A number of studies have demonstrated that individuals with metabolic syndrome and diabetes have an increased risk of cancer of the pancreas, rectum and endometrium [8–10]. In this setting, elevated blood glucose has been associated with increased cancer risk in a number of prospective studies. Diabetes is now a recognized risk factor for cancer [8,11–15]. A large collaborative study of over 550,000 patients in six prospective cohort studies as part of the Metabolic Syndrome and Cancer Project (Me-Can) demonstrated that abnormal glucose metabolism—independent of BMI—was associated with increased cancer risk at various sites in both men and women [16]. A follow-up study from the same collaborative group demonstrated that each standard deviation increase in a metabolic risk score was associated with 56% increased risk in endometrial adenocarcinoma. Within this cohort, the association between BMI and cancer incidence was much weaker than the association between serum glucose levels and cancer incidence [17]. Furthermore, BMI was not associated with cancer mortality, while elevated blood glucose was a significant predictor of cancer mortality. Int. J. Mol. Sci. 2020, 21, 1241 3 of 19 4. Impact of Weight Loss on Cancer Risk The epidemiological links between obesity, metabolic dysfunction and cancer development are clear. What, then, is the impact of weight loss in terms of cancer risk? Observational studies have shown a decrease in cancer-related mortality for those who lose weight, to a larger extent for women than for men [18,19]. Larger cohort studies demonstrate that metabolic surgery decreases cancer incidence and mortality when compared to obese controls [20]. The Swedish Obese Subjects (SOS) study demonstrates decreased incidence of cancer in women who underwent metabolic surgery when compared with biologically matched controls [21] a finding reciprocated in a larger American cohort which demonstrated similar results, with a marked decreased risk for obesity-related cancers [22]. A recent small (n = 6) prospective cohort study demonstrated the ability of metabolic surgery to reverse complex atypical hyperplasia of the endometrium, a known endometrial cancer precursor. Hyperplasia resolved in the majority of cases (5/6; 83%) with 3/6 (50%) resolving with metabolic surgery alone [23]. Endometrial biopsies taken before and after surgery demonstrated reduced expression of oestrogen and progesterone receptors at 2 and 12 months after metabolic surgery and a 17% reduction in the Ki-67 proliferation index seen 12 months after metabolic surgery.
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