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

ESCC is prevalent worldwide, and chemotherapy, particularly cisplatin-based treatments, is a primary therapeutic approach. However, chemoresistance is a major issue leading to poor outcomes. GDF15, a member of the TGF-β cytokine superfamily, has been implicated in malignancy and chemoresistance in various cancers.

Xiaobing Wang et al., at State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China, conducted a study to  investigate the role of growth differentiation factor 15 (GDF15) in esophageal squamous cell carcinoma (ESCC), a common and aggressive form of esophageal cancer. The study utilized cell lines KYSE30 and KYSE150, with experiments involving the application of GDF15, neutralization antibodies, and chemotherapeutic agents. Bioinformatics analysis, gene deletion via CRISPR/Cas9, Western blot, mRNA sequencing, quantitative real-time PCR, cell viability assays, flow cytometry, immunohistochemistry, and metabolomic profiling were among the methods employed.

GDF15 expression was found to be upregulated in ESCC and correlated with chemoresistance. GDF15 was shown to negatively regulate the chemosensitivity of ESCC cells to cisplatin both in vitro and in vivo. The study revealed that GDF15 modulates drug metabolism by activating the AKT pathway through TGFBR2, indicating a role in chemoresistance.

The findings suggest that GDF15 could be a predictor of chemoresistance and an effective target for ESCC treatment. The study highlights the potential of targeting the GDF15/TGFBR2/AKT/UGT1A signaling axis to enhance the response to cisplatin in chemoresistant ESCC.

Inhibition of GDF15 may sensitize ESCC cells to cisplatin cytotoxicity, and targeting this pathway could be a promising therapeutic strategy.