PDHX pyruvate dehydrogenase protein X (PDHX), as a non-catalytic subunit ofPDHc, is located in the mitochondrial matrix and at the center of mitochondrial energy metabolism. Its role in tumorigenesis and development seems to be very complex, because it has both carcinogenic and tumor inhibitory effects in cancer. For example, as a direct target gene of mir-26a and mir-27b, PDHX down-regulates the growth and metastatic potential of colorectal and breast cancer cells(15, 18). It is also reported that PDHX, as an important metabolic gene in esophageal squamous cell carcinoma, is necessary to maintain the activity of PDHc and produce ATP. Its knockdown inhibits the proliferation and tumor growth of esophageal squamous cell carcinoma stem cell (CSCs)(27). In non-tumor diseases, PDHX has also been reported, for example, as an important component of PDHc activity, PDHX mutation plays an important role in congenital lactic acidosis(19). There is some synergism between lupus erythematosus and the expression of inflammatory factor CD44 in the pathogenesis of lupus erythematosus(20). From these studies, we can find that PDHX seems to play some important roles in the occurrence and development of tumors and metabolic and immune diseases. Based on the study of PDHX in tumor and non-tumor metabolic and immune diseases, we believe that PDHX may play some role in immune evasion of gastric cancer, so as mentioned above, we used Timer2.0 database to study the potential relationship between different levels of immune cell infiltration and PDHX gene expression in different types of TCGA tumors. In addition, as the hub of glycolysis and tricarboxylic acid cycle, the low expression of PDHX in cancer cells also inhibits the activity of PDHc. As a result, pyruvate accumulates upstream, reducing downstream acetyl CoA production and diverting it to lactic acid production, providing continuous glycolysis flux or feeding cells for biomolecule synthesis (Fig. 5). The loss of PDH function also leads to a decrease in aerobic respiration, which indicates that cancer cells become more dependent on the aerobic glycolysis pathway. This is consistent with previous reports, which confirmed that impaired PDHc function can trigger malignant metabolic phenotypes of tumors(28). This change, as well as the increase in lactic acid production, is a unique feature of the Weinberg effect. A series of hypotheses put forward so far in this field suggest that this energy metabolic remodeling is beneficial to the growth of tumor volume(29).
Energy metabolism remodeling is the characteristic of energy metabolism of tumor cells and their neighboring cells in tumor microenvironment (TME). The latter includes stromal fibroblasts and adipocytes, which differentiate into cancer-associated fibroblasts (CAF) and cancer-associated adipocytes (CAA) as well as immune infiltrating cells. They cooperate with stromal cells to provide a favorable living environment for tumor growth. Cancer-associated fibroblasts (CAF) are located near the tumor and account for a large part of the tumor mass. It is reported that CAF accounts for 80% of tumor masses in breast and pancreatic cancer(30). CAF has its genetic characteristics and has the ability to influence tumorigenesis, invasion and progression by releasing cytokines, chemokines and angiogenic factors(31). It should also be noted that very similar to tumor cells, CAF undergoes metabolic remodeling and changes to glycolysis phenotype, which enables them to produce high-energy metabolites such as lactic acid, pyruvate and ketone bodies, which provides fuel for neighboring tumor cells(32). Energy metabolism reprogramming is related to TME acidification, and TME acidification is also an important feature of tumor progression(33, 34). And the establishment of tumor acidic microenvironment (TME) reduces the efficiency or loss of function of most anti-tumor immune cells(35). In addition to inhibiting glycolysis of PDHX, tumors, it may also be disturbed by any intermediate step in glucose metabolism. For example, it is known that inhibiting hexokinase (36)or any other enzyme that catalyzes the subsequent reaction of glucose metabolism can enhance the anticancer effect(37, 38). Removing the regulation of tumor glycolysis by targeting glycolytic enzymes other than PDHX may also have additional ideal results. This is mainly due to the "feedback" inhibition mechanism of glucose metabolism. Specifically, the metabolites of the intermediate steps of glycolysis accumulate due to the inhibition of specific enzymes, and finally block or slow down the rate of glucose catabolism in the way of negative feedback. Therefore, the destruction of tumor glycolysis seems to reduce the oxidation and utilization of glucose.
Although aerobic glycolysis may not produce as much ATP as mitochondria, it has the advantages of higher efficiency, use of unconventional nutrients and non-dependence on oxygen. Moreover, malignant tumor cells for the purpose of self-proliferation, its gene mutation will be more conducive to the effective acquisition of macromolecular substances for self-proliferation, rather than energy production. The rapid proliferation of malignant tumor cells also needs a lot of energy, but its degree of differentiation is low, and it may lack the key enzymes necessary for the process of oxidative phosphorylation, so we have to choose glycolysis to supply energy. Compared with the oxidative phosphorylation of glucose, glycolysis can be completed in the cytoplasm without entering the mitochondria for metabolism, reducing the key enzymes needed in the metabolic process. At the same time, because of its simple metabolic process, it can provide energy for rapidly proliferating cells more quickly(39). The relatively hypoxic environment of tumor tissue makes glycolysis an effective choice, and the lactic acid it produces can provide an acidic microenvironment for tumor cells. This acidic microenvironment can induce immune escape, promote invasion and metastasis of tumor cells, while at the same time promote apoptosis of normal cells, turn off DNA repair mechanism, and inhibit apoptosis of tumor cells(40). The decrease of oxidative phosphorylation in tumor cells leads to a decrease in the production of reactive oxygen species (ROS) to some extent, thus reducing the killing effect on tumor cells(41–43). Malignant tumor cells choose glycolysis pathway to provide themselves with raw materials and energy for proliferation, and produce acidic microenvironment and reduce reactive oxygen species (ROS) to inhibit apoptosis, which is not only an important cause of tumorigenesis, to a certain extent, it is more likely to be the result of tumor cell evolution, which will be more conducive to tumor cell invasion, proliferation and metastasis.
Gastric cancer ,as fifth-largest cancer in the world and third-largest cancer in China, has the characteristics of high morbidity and high mortality(4, 5). With the invasive invasion or lymphatic metastasis of gastric cancer, although traditional therapy, such as surgery, radiotherapy, chemotherapy or traditional Chinese medicine, is used to enhance the therapeutic effect, the therapeutic effect of gastric cancer is still not satisfactory(44). In the face of such a severe situation, it is urgent to develop new treatment methods to improve the diagnosis rate and judge the prognosis of gastric cancer. In order to make significant improvements in the treatment of gastric cancer, we must be willing to study new and unconventional treatment methods. There is growing evidence that abnormal cell metabolism is a basic component of tumor composition, which increases the possibility that treatments developed for this feature will be significantly effective in the future(45). In fact, it has been added to the list of cancer markers by Hanahan and Weinberg, so its importance in the pathogenesis of cancer is evident(46).At present, some limited evidence shows that metabolically active drugs have therapeutic effects on cancer. For example, clinical studies have reported that diabetics who use metformin to control hyperglycemia have a lower risk of breast cancer(47, 48)
In short, the energy metabolism of tumor cells is reconstructed, the expression of enzymes related to glycolysis decreases or increases, and some genes are mutated, which may become targets of anti-tumor therapy. Hope and challenges coexist, tumor is essentially a group of cells with metabolic changes, and the treatment of tumor cell metabolism may become a new milestone in anti-tumor therapy.
Clinical Medical College, Yangzhou University, Yangzhou 225001, China.
Biao Sun, Li Bao ,Daorong Wang
Dalian Medical University, Dalian116044, China.
Ziyang Long, Cangyuan Zhang
Northern Jiangsu People’s Hospital, Yangzhou 225001, China.
Qiannan Sun, Jun Ren, Daorong Wang
General Surgery Institute of Yangzhou, Yangzhou University,Yangzhou 225001,China.
Qiannan Sun, Jun Ren,Daorong Wang
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.