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

Abstract

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.

Keywords

GDF15 / esophageal squamous cell carcinoma / chemoresistance / cellular metabolism / TGFBR2 / AKT

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Acknowledgements

We thank Dr. Xiaohui Liu at the Metabolomics Center at Tsinghua University National Protein Science Facility (Beijing) for her technical help. This work was supported by the National Key R&D Program of China (No. 2021YFC2501004), the National Natural Science Foundation of China (Nos. 82172988, 81772490 and 81502023), and the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (Nos. 2021-1-I2M-014 and 2021-1-I2M-067).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-022-0949-7 and is accessible for authorized users.

Compliance with ethics guidelines

Yingxi Du, Yarui Ma, Qing Zhu, Yong Fu, Yutong Li, Ying Zhang, Mo Li, Feiyue Feng, Peng Yuan, and Xiaobing Wang declare that no conflict of interest exists. All animal protocols had received approval from the Animal Ethical Committee of the Cancer Hospital, Chinese Academy of Medical Sciences (Beijing, China).

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