Abstract
Thymopentin (TP5) is an immunomodulatory pentapeptide that has been widely used in malignancy patients with immunodeficiency due to radiotherapy and chemotherapy. Here, we propose that TP5 directly inhibits the stemness of colon cancer cells HCT116 and therefore enhances the cytotoxicity of oxaliplatin (OXA) in HCT116 cells. In the absence of serum, TP5 was able to induce cancer stemness reduction in cultured HCT116 cells and significantly reduced stemness-related signals, such as the expression of surface molecular markers (CD133, CD44 and CD24) and stemness-related genes (ALDH1, SOX2, Oct-4 and Nanog), and resulted in altered Wnt/β-catenin signaling. Acetylcholine receptors (AchRs) are implicated in this process. OXA is a common chemotherapeutic agent with therapeutic effects in various cancers. Although TP5 had no direct effect on the proliferation of HCT116, this pentapeptide significantly increased the sensitivity of HCT116 to OXA, where the effect of TP5 on the stemness of colon cancer cells through stimulation of AchRs may contribute to this process. Our results provide a promising strategy for increasing the sensitivity of colon cancer cells to chemotherapeutic agents by incorporating immunomodulatory peptides.
Highlights
Colorectal cancer (CRC) is one of the common malignant tumors of the gastrointestinal system, and the current 5-year survival rate of colorectal cancer is 66% worldwide, but the 5-year survival rate of patients with advanced disease is only 13% (Miller et al, 2019)
The number of cancer stem cell spheroids was significantly less in HCT116 cells treated with TP5 than in the control group, and the spheroid formation rate was significantly decreased in a concentration-dependent manner (Figures 1A,B), indicating that TP5 reduced the stemness of HCT116 cancer stem cells and inhibited the self-renewal and proliferation ability of cancer stem cells
To further verify the effect of TP5 on colon cancer stem cells, we used flow cytometry to detect the expression of cancer stem cell markers CD24, CD44 and CD133, which are surface markers that can be expressed by colon cancer stem cells (Jaggupilli and Elkord, 2012; Sahlberg et al, 2014)
Summary
Colorectal cancer (CRC) is one of the common malignant tumors of the gastrointestinal system, and the current 5-year survival rate of colorectal cancer is 66% worldwide, but the 5-year survival rate of patients with advanced disease is only 13% (Miller et al, 2019). The main treatments for colorectal cancer include surgical resection, radiotherapy, and immune anticancer therapy (Ciombor et al, 2015). Numerous studies have shown that cancer stem cells (CSCs) are the core factor leading to postoperative recurrence, radiotherapy insensitivity, and immunotherapy resistance in tumor patients (Regan et al, 2017; Tosoni et al, 2017; Luo et al, 2018). Cancer stem cells exhibit a high degree of insensitivity to chemotherapy and radiotherapy (Zhao, 2016). Cancer stem cells are theoretically mostly in a quiescent state, while oncologic therapies such as radiotherapy and chemotherapy target proliferating tumor cells (Phi et al, 2018). In many colorectal cancer patients, good therapeutic results can be achieved at the beginning of drug administration, an avalanche of multidrug resistance soon occurs and tumors progress rapidly (Hervieu et al, 2021)
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