Studies on the effects of exercise on cancer have dramatically increased since the 1990s. According to many studies, there is a link between physical activity and a reduction in the risk of colon cancer. It shows that performing of physical activity before the diagnosis of colon cancer reduces about 50% of the risks of this cancer (compared with those who are not active). In relation to the affecting biological mechanisms on the effect of exercise on colon cancer Studies are limited. Therefore, the purpose of this study was to investigate the effect of aerobic interval training before and after tumor induction in the colon and its effect on the metabolism of lactate and glucose by regulation of p53.
Induction of a colon tumor caused a significant increase in animal weight. Also tumor group had a significant increase in colon weight and colon length. Examination of the tumor size also showed that TE and ETE groups showed a significant decrease in tumor volume compared to tumor group (Table 1). Thus all of this change show induction of tumor compares to control group and prove tumor induction.
Increasing lactate exchange in tumor cells increases the metabolic rate of cancer cells and increases the function of these cells. One of the most important regulators in the transfer of lactate between cancer cells, especially colon cancer, is monocarboxylate transporter, especially MCT-1. According to the results of this study, it was found that the colon tumor has an increase in MCT-1 (Fig. 2). As stated, the increase in MCT-1 in tumor cells leads to an increase in lactate in the tumor microenvironment. Lactate causes expression of HIF-1 in many cancer cells and HIF-1 itself are effective in increasing MCT-1. On the other hand, the increase in lactate for tumor cells is critical because lactate increases cellular migration, angiogenesis, immune escape, and radio resistance. These conditions are suitable for cancer development and reduction of this agent can be a therapeutic target. In the present study, it was determined that aerobic interval training before and after tumor induction significantly decreased MCT-1, that this reduction was higher in the pre-tumor exercise group (ET) (Fig. 2). Stopping or reducing the activity of the MCT-1 Restricted Feeding the cancer cells and places these cells in starvation state. Because in cancer cells, MCTs allow to lactate travel outside the cell and play important role as a mediator of carcinogenesis in other adjacent cancer cells. For this reason, targeting MCTs has a therapeutic role in cancer cells. Inhibition of MCT-1 inhibits tumor growth and carcinogenesis [42, 43]. Therefore, exercise at the cellular level of tumor has limited lactate transport, which is very suitable for cancer treatment. It has been shown that MCT-1 expression regulate by c-MYC in a variety of cancers. However, exercise can reduce the degradation activity of c-MYC. However, in the present study, c-MYC activity was not investigate. Several studies have been conduct on the effect of exercise (in healthy subjects) and colon cancer prevention[27, 45]. In human studies, it has been confirmed that exercises usually accompanied with increasing the quality of life and improve of mental states. These factors although reducing the risk factors of cancer, they effective in improving the physical fitness before the onset of cancer. However, studies are limited in relation to the signaling pathways affecting the MCT-1 with exercise. One of the most effective genes in tumor suppression is p53. Studies show that exercise can cusses increase the tumor suppressor gene, i.e P53. In fact, the mutation of tumor suppressor, directly increases the expression of MCTs, which has been shown this action reprogram the cancer cells towards glycolysis and produce lactate only because the effect of Warburg does not end.
P53 controls the levels of lactate in tumor cells by controlling MCT-1. There is a direct correlation between p53 function and MCT-1 expression. Under hypoxic conditions, reduction in p53, promotes the expression of MCT-1 and, export of lactate produced by the rise of glycolytic flux in both vitro and vivo. In the present study, changes in p53 mRNA and MCT-1 confirmed this issue. P53 interacted directly with the MCT-1 gene promoter and altered MCT1 mRNA stabilization. Under hypoxic conditions and reducing p53 in tumor cells, NF-KB promotes expression of MCT-1, which increases its levels. Following an increase in glucose consumption in tumor cell, up regulation of MCT-1 under reduced p53 conditions, promotes lactate Import and enhances cell proliferation by increasing mitochondrial respiration[17, 39]. The researchers suggested that increasing the MCT-1 in conditions of p53 deficiency, allows the tumors to adapt to metabolic needs by facilitating lactate export .That these results are consistent with the results of this study. In this study, levels of p53 mRNA were also evaluated. In the healthy groups of the present study, exercise showed a significant increase in colon p53 mRNA compared to healthy animal in control group (Fig. 5). However, tumor induction severely reduced p53 mRNA. Comparing exercise before and after the tumor, was found that exercise before tumor induction had better control in improvement of inhibiting p53 mRNA and increase in p53 mRNA was higher in the ET group. Although exercise after tumor induction (TE) also increased significantly in the p53 mRNA compared to the tumor group, but this increase was lower than the ET group. P53 directly activates the expression of many genes that are used to regulate the cell cycle and apoptosis through binding to p53 DNA-binding sites. P53 plays a vital role in regulating the stopping of the cell cycle and inducing carcinoma cell apoptosis. Thus it can have an anticancer role. P53 inhibits cell cycle progression in the G1 or G2 / M phase by inducing p21 cell cycle inhibitors and enhancing apoptosis by inducing Bax preopoptotic expression. Previous studies have shown that treatment through polyphenols causes p53 up regulation, and p53 can regulate p21, PUMA, and Bax in human colon cancer, which is effective in stopping the tumor. It has been state that p53 activation plays a role in the reduction of glycolysis. Protein P53 inhibits the expression of several carriers of glucose, including GLUT-1 and GLUT4.
In consideration of GLUT-1, it was also found that the tumor caused a significant increase in this protein in the colon tissue compared with healthy control and exercise groups (Fig. 3). This increase is normal, due to the high metabolism of cancer cells and the Warburg effect. GLUT-1 is an important isoform in human colon cancer cells. It is stated that under hypoxic conditions, cancer cells often express high amount of GLUT-1. Hypoxic microenvironment of tumor cusses induces of hypoxia induce factor and overexpression of HIF-1a and HIF-1B subunit. HIF-1 activates several signaling pathways in cancerous cells. It has been shown that GLUT-1 levels increase both mRNA levels and protein levels in hypoxia conditions. In other words, HIF-1 causes upregulation expression of GLUT-1 in tumor cell environments. That increased the GLUT-1 tumor group in present study is also justifiable. However, the extent of tumor microenvironment hypoxia, was not investigated in this study. Also, in line with the results of this study, Graziano et al. (2017) showed that GLUT-1 increased in colorectal cancer, which increased glucose consumption in cancer cells. These researchers increase of GLUT-1 attributed to increase in RAS oncogenes, because there is a correlation between the positive mutation of the RAS tumor and the expression of the GLUT-1 mRNA. It is stated that inhibition and reduction of GLUT-1 activity in tumor cells through various supplements and medications is effective in the treatment of cancer, and it restricts tumor growth. In the present study, it was found that exercise activity prior to tumor induction (ET) did not significantly decrease in GLUT-1 colon tumor, but when animal’s first tumor and then exercise (TE), the amount of GLUT-1 tumors decreased, that this decrease was significant (Fig. 2). In experimental examples it is stated that down regulation or inhibition of glycolysis through the GLUT blocker. Which it was confirmed in the present study and exercise can block or decrease the GLUT-1 in tumor colon (in TE group).
Regarding Fig. 3, in addition to the results of GLUT-1 and MCT-1, in the tumor group, a significant increase in PFK-1 was found in the tumor group as a key regulator of glycolysis. However, aerobic interval training before and after tumor induction reduced the amount of this enzyme (significant decrease) (Fig. 4). AMPK activates PFK. Exercise by AMPK can also change the PFK-1 levels in tumor cells. It can also be assumed that changes in levels of tumor PFK-1 with aerobic interval training can be attributed to p53 changes. Because a recent study has shown that p53 causes dermalogue of PFKFB4, one of the enzymes controlling levels of fructose 2–6 bisphosphate, which is the major alloystic regulator of glycolysis. One of the metabolic genes regulated with p53 is TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) that inhibits glycolysis in the allosteric manner through PFK-1 . Inhibition of PFK-1 with TIGAR can indirectly increase the antioxidant capacity by shunting glucose to the pentose phosphate pathway for glutathione biosynthesis. Therefore, TIGAR inhibits tumor DNA by reducing the oxidative damage. On the other hand, a subsequent study has shown that the overexpression of TIGAR in human colon cancers can promote both tumor genesis and the regeneration of normal tissue, demonstrating that cancer cells can also benefit from the metabolic activities of TIGAR. Despite this, the studies are controversial. On the other hand, only p53 mRNA was consider in this study and TIGAR levels of the tumor was not measured. Therefore, it is suggested that the PFK variations in the present study may be influenced by p53 and TIGAR, but it’s suggested that in subsequent studies, TIGAR values should also be evaluated.
Aerobic interval training can be countered with progression of Warburg effects of cancer cell. Several evidence has shown that cancer patients who are exercising can had better cope with cancer , Because the survival rate of cancer patients increases with physical activity and exercise. However, the molecular and cellular mechanism how that exercise is involved in cancer is still unclear. It has been argued that aerobic exercise improves mitochondrial function and lactate clearance capacity, as it increases fat oxidation capacity and decreases glycolysis in cancer cell. In fact, exercise can have anti-Warburg effects in tumor microenvironment. Christine et al (2002) argued that the biologic effects of exercise on tumor cell can be different and limited research has been done on this issue. The researchers showed that in colon cancer, gastrointestinal transit time is reduced, which exercise can increase the activity of intestinal movements. On the other hand, colon cancer decreases the proportion of prostaglandins. Studies have shown that it high intensity exercise increases the of prostaglandin F activity, that this action suppressing the proliferation of colonic cells, increases the gat mobility, while not increasing PGE2, which can affect the proliferation of colonic cells .