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Recently, the British Journal of Cancer (British Journal of Cancer) and Cancer Research UK (Cancer Research UK) jointly published a report titled "Heat stress is involved in TRPV2 through HSP70/HSP70/ 27 and PI3K/Akt/mTOR pathway promotes tumorigenesis in esophageal squamous cell carcinoma” (Thermal stress involved in TRPV2 promotes tumorigenesis through the pathways of HSP70/27 and PI3K/Akt/mTOR in esophageal squamous cell carcinoma.
Esophageal cancer is one of the most common malignant tumors, threatening the life and health of resident.
Based on years of research on transient receptor potential ion channels (TRP), Li Zhiyuan's research team detected the expression and function of thermosensitive TRPV in human esophageal squamous epithelial cells, and found that compared with non-tumor tissues, ESCC cells and clinical ESCC samples The expression of TRPV2 was significantly up-regulated, and calcium imaging experiments confirmed that its functional activity was correspondingly enhance.
Further studies have found that short and frequent stimulation of ESCC cells with heat (54°C) that activates TRPV2 channels can significantly enhance malignant cell behaviors such as ESCC cell proliferation, invasion, and angiogenesis in vitro, while in viv.
Mechanistically, TRPV2 can up-regulate heat shock factor 1 (HSF1) and promote the transcriptional expression of heat shock proteins 70 and 27 (HSP70/27) after ESCC cells are activated by heat stress, thereby promoting the tumorigenicity of ESCC; At the same time, PI3K is significantly activated in this process, which in turn activates its downstream signaling protein PDK1, and then PDK1 upregulates the functions of target proteins AKT1 and mTORC On the contrary, the negative regulatory protein PTEN of PI3K is downregulated and inhibited, indicating that PI3K signaling is amplified by PTEN, thereby significantly promoting The tumorigenicity and invasiveness of ESC.
The study also found that pan-PI3K/mTOR kinase inhibitors VS5584 and Oroxin B can significantly inhibit the proliferation of ESCC cells overactivated by TRPV2, and the combination of the two with Tranilast can further weaken the proliferation ability of ESCC cells, suggesting that Tranilast combined with pan-PI3K/mTOR Inhibitors may be useful in the treatment of ESC.
It is worth noting that the activation temperature of the TRPV2 channel found in this study is 54°C, which is lower than the dietary temperature in many populations and well below the high temperature dietary risk temperature recommended by the International Agency for Research on Cancer (65°C), so the study A new direction is proposed for the prevention and treatment of esophageal squamous cell carcinom.
The research work was funded by the National Natural Science Foundation of China, Guangdong Province and the Frontier Research Project of the Bio Island Laboratory, and was supported by the Li Ka Shing School of Medicine of the University of Hong Kong, the Second Xiangya Hospital of Central South University and the Hunan Cancer Hospita.
Paper link:diagram of the involvement of heat stress in TRPV2 in promoting tumorigenesis of esophageal squamous cell carcinoma
