GDF15 negatively regulates chemosensitivity via TGFBR2-AKT pathway-dependent metabolism in esophageal squamous cell carcinoma / 医学前沿

Treating patients with esophageal squamous cell carcinoma (ESCC) is challenging due to the high chemoresistance. Growth differentiation factor 15 (GDF15) is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research. In this study, the link between GDF15 and chemotherapy resistance in ESCC was further explored. The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies. ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response. GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2. Through an in vivo study, we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin. Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A. AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A, indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin. The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy, resulting in beneficial therapeutic outcomes.

Astragalus polysaccharides suppressed cisplatin-resistance of colorectal cancer TH-29/DDPcells via regulating miR-20a/TGFBR2 axis / 中国肿瘤生物治疗杂志

@# Objective: To investigate the effect of astragalus polysaccharides (APS) on proliferation, invasion, apoptosis and drugresistance of cisplatin-resistant colorectal cancer (CRC) HT-29/DDP cells through regulating miR-20a/TGFBR2 axis, and to explore the possible mechanism. Methods: Human CRC HT-29 cells and HT-29/DDP cells were used as non-drug resistant and resistant cell models, respectively; HT-29/DDP cells were randomly divided into four groups, including untreated (HT-29/DDP) group, APS treatment group, miR-20a mimics + APS group, and si-TGFBR2 + APS group. qPCR and Western blotting were applied to detect the expressions of miR-20a and TGFBR2 in HT-29/DDP cells treated with different concentrations ofAPS (0, 0.5, 1.0, 1.5 and 2.0 mg/ml). Subsequently, dual luciferase reporter gene assay was used to verify whether TGFBR2 was a target gene of miR-20a. In addition, CCK-8, Transwell andAnnexin V-FITC/PI double staining were applied to examine the effect ofAPS on proliferation, invasion and apoptosis of HT29/DDP cells. Furthermore, subcutaneous HT-29/DDP cell xenograft model was established on nude mice, and the effect ofAPS on the growth of transplanted tumor was observed. Results: APS significantly inhibited the proliferation of HT-29/DDP cells in a dose-dependent manner (P<0.01). Meanwhile, the expression of miR-20a was down-regulated in HT-29/DDP cells treated with APS, while the expression of TGFBR2 was significantly up-regulated (all P<0.01). Additionally, dual luciferase reporter gene assay result showed that TGFBR2 was a direct target of miR-20a in HT-29/DDP cells and its expression was suppressed. Furthermore, APS could enhance the drug sensitivity of HT-29/DDP cells through downregulating the inhibitory effect of miR-20a on TGFBR2 expression, thereby suppressed proliferation and invasion, and induced apoptosis of HT-29/DDP cells in vitro and in vivo. It was also found that this effect was related with the suppression of PCNA and Bcl-2 proteins and promotion of Bax and Caspase-3 proteins. Conclusion: APS reverses the resistance of HT-29/DDPcells to cisplatin by down-regulating the inhibitory effect of miR-20a on TGFBR2 expression.