New strategies for targeting glucose metabolism-mediated acidosis for colorectal cancer therapy.

Colorectal cancer (CRC) is a heterogeneous group of diseases that are the result of abnormal glucose metabolism alterations with high lactate production by pyruvate to lactate conversion, which remodels acidosis and offers an evolutional advantage for tumor cells, even enhancing their aggressive phenotype. This review summarizes recent findings that involve multiple genes, molecules, and downstream signaling in the dysregulated glycolytic pathway, which can allow a tumor to initiate acid byproducts and to progress, thereby resulting in acidosis commonly found in the tumor microenvironment of CRC. Moreover, the relationship between CRC cells and the tumor acidic microenvironment, especially for regulating lactate production and lactate dehydrogenase A levels, is also discussed, as well as comprehensively defining different aspects of glycolytic pathways that affect cancer cell proliferation, invasion, and migration. Furthermore, this review concentrates on glucose metabolism-mediated transduction factors in CRC, which include acid-sensing ion channels, triosephosphate isomerase and key glycolysis-related enzymes that regulate glycolytic metabolites, coupled with the effect on tumor cell glycolysis as well as signaling pathways. In conclusion, glucose metabolism mediated by glycolytic pathways that are integral to tumor acidosis in CRC is demonstrated. Therefore, selective metabolic inhibitors or agents against these targets in glucose metabolism through glycolytic pathways may be clinically useful to regulate the tumor's acidic microenvironment for CRC treatment and to identify specific targets that regulate tumor acidosis through a cancer patient-personalized approach. Furthermore, strategies for modifying the metabolic processes that effectively inhibit cancer cell growth and tumor progression and activate potent anticancer effects may provide more effective antitumor prospects for CRC therapy.

Wang G ，Wang JJ ，Yin PH ，Xu K ，Wang YZ ，Shi F ，Gao J ，Fu XL ... -  《-》

Targeting Strategies for Glucose Metabolic Pathways and T Cells in Colorectal Cancer.

Colorectal cancer is a heterogeneous group of diseases that result from the accumulation of different sets of genomic alterations, together with epigenomic alterations, and it is influenced by tumor-host interactions, leading to tumor cell growth and glycolytic imbalances. This review summarizes recent findings that involve multiple signaling molecules and downstream genes in the dysregulated glycolytic pathway. This paper further discusses the role of the dysregulated glycolytic pathway in the tumor initiation, progression and the concomitant systemic immunosuppression commonly observed in colorectal cancer patients. Moreover, the relationship between colorectal cancer cells and T cells, especially CD8+ T cells, is discussed, while different aspects of metabolic pathway regulation in cancer cell proliferation are comprehensively defined. Furthermore, this study elaborates on metabolism in colorectal cancer, specifically key metabolic modulators together with regulators, glycolytic enzymes, and glucose deprivation induced by tumor cells and how they inhibit T-cell glycolysis and immunogenic functions. Moreover, metabolic pathways that are integral to T cell function, differentiation, and activation are described. Selective metabolic inhibitors or immunemodulation agents targeting these pathways may be clinically useful to increase effector T cell responses for colorectal cancer treatment. However, there is a need to identify specific antigens using a cancer patient-personalized approach and combination strategies with other therapeutic agents to effectively target tumor metabolic pathways.

Wang G ，Wang JJ ，Guan R ，Sun Y ，Shi F ，Gao J ，Fu XL ... -  《-》

The acid-sensing ion channel, ASIC2, promotes invasion and metastasis of colorectal cancer under acidosis by activating the calcineurin/NFAT1 axis.

Zhou ZH ，Song JW ，Li W ，Liu X ，Cao L ，Wan LM ，Tan YX ，Ji SP ，Liang YM ，Gong F ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

Inhibitory ASIC2-mediated calcineurin/NFAT against colorectal cancer by triterpenoids extracted from Rhus chinensis Mill.

Studies have shown that the etiology and pathogenesis of colorectal cancer are closely related to the tumor microenvironment, and the cancer tissue is still in the state of "energy deficit" and has to promote energy generation through high glycolysis. Rhus chinensis Mill is a Chinese herbal medicine used to treat various types of solid tumors in China. Colorectal cancer (CRC) is a heterogeneous disease group caused by abnormal changes in glucose metabolism resulted in lactic acid production, which remodels acidosis. Although previous studies have shown that the active compounds of Rhus chinensis Mill. can inhibit the proliferation of tumor cells, whether its triterpenoids could effectively regulate glycolysis involved in CRC have not been systematically investigated. In this study, the extraction of triterpenoids extract from Rhus chinensis Mill. was obtained, and cell viability assay, the percentage of apoptosis for CRC cells were counted, and matrigel invasion assay and production of lactic acid and glucose uptake assay was determined. we further examined the expression of the key glycolytic enzymes and acid-sending ion channel (ASIC) family members of SW620 cells, and some key proteins in the glycolytic pathway were further verified. Notably, triterpenoids (TER) of Rhus chinensis Mill. showed effective anti-proliferative activity and significantly altered protein levels associated with CRC cell survival and glycolysis metabolism. TER could down-regulate the expression of ASIC2, in CRC SW620 cell line. Most importantly, the levels of ASIC2 and calcineurin/nuclear factor of activated T cells (NFAT) were also down-regulated by TER. Furthermore, inhibition of activated the ASIC2-mediated calcineurin/NFAT1 pathway and target gene transcript expression of MMP-2 and MMP-9 in parallel to reduce, and resulted in the reduced invasion ability by TER treatment. The potential pathways and targets that involved in glycolysis to excert the anti-CRC effects of main compounds in triterpenoids of Rhus chinensis Mill. were predicted by network pharmacology methods. Our findings thus provided rational evidence that inhibition of the ASIC2-induced calcineurin/NFAT pathway by triterpenoids in Rhus chinensis Mill. profoundly suppressed cell growth and invasion in CRC, which target alternative glycolysis in colorectal tumor cells, may be a useful adjuvant therapy in the treatment of colorectal cancer.

Wang G ，Wang YZ ，Yu Y ，Wang JJ ... -  《-》

The critical role of calcineurin/NFAT (C/N) pathways and effective antitumor prospect for colorectal cancers.

Transcription factors (TFs) like a nuclear factor of activated T-cells (NFAT) and its controller calcineurin are highly expressed in primary intestinal epithelial cells (IECs) due to delamination, damage by tumor-associated flora and selective activation in the intestinal tract tumor are crucial in the progression and growth of colorectal cancer (CRC). This study sought to summarize the current findings concerning the dysregulated calcineurin/NFAT (C/N) signaling involved in CRC initiation and progression. These signalings include proliferation, T-cell functions, and glycolysis with high lactate production that remodels the acidosis, which genes in tumor cells provide an evolutionary advantage, or even increased their attack phenotype. Moreover, the relationship between C/N and gut microbiome in CRC, especially role of NFAT and toll-like receptor signaling in regulating intestinal microbiota are also discussed. Furthermore, this review will discuss the proteins and genes relating to C/N induced acidosis in CRC, which includes ASIC2 regulated C/N1 and TFs associated with the glycolytic by-product that affect T-cell functions and CRC cell growth. It is revealed that calcineurin or NFAT targeting to antitumor, selective calcineurin inhibition or targets in NFAT signaling may be useful for clinical treatment of CRC. This can further aid in the identification of specific targets via cancer patient-personalized approach. Future studies should be focused on targeting to C/N or TLR signaling by the combination of therapeutic agents to regulate T-cell functions and gut microbiome for activating potent anticancer property with the prospect of potentiating the antitumor therapy for CRC.

Gang W ，Yu-Zhu W ，Yang Y ，Feng S ，Xing-Li F ，Heng Z ... -  《-》