Lee Jaehak, Kim Ilju, Ryu Junsun, Eling Thomas, Baek Seung Joon
Laboratory of Signal Transduction, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea.
Department of Otolaryngology-Head and Neck Surgery, Center for Thyroid Cancer, Research Institute and Hospital, National Cancer Center, Goyang-si, Gyeonggi-do, Korea.
Cell Death Dis. 2025 May 2;16(1):355. doi: 10.1038/s41419-025-07695-w.
NAG-1/GDF15, a tumor suppressor, is synthesized as a pro-form in colorectal cancer (CRC) cells and undergoes cleavage to generate its mature form. While the biological function of pro-NAG-1/GDF15 remains unclear, our study reveals its crucial role in suppressing oncogenic signaling. We demonstrate that pro-NAG-1/GDF15 is predominantly retained within cells, whereas its mature form is secreted into the media. The expression of NAG-1/GDF15, or uncleavable R193A mutant, inhibits β-catenin and NF-κB signaling, key pathways in CRC progression. Mechanistically, the pro-NAG-1/GDF15 interacts with EpCAM, preventing its cleavage and nuclear translocation, thereby reducing β-catenin and NF-κB activity. This inhibition correlates with decreased expression of oncogenic targets such as cyclin D1 and c-myc. In vivo, NAG-1/GDF15 expression significantly reduces tumor growth in cancer xenograft models, accompanied by decreased proliferation and increased apoptosis. Furthermore, analysis of public datasets suggests that high NAG-1/GDF15 expression is associated with improved CRC patient survival. These findings highlight NAG-1/GDF15 via the formation of pro-NAG-1/GDF15 as a promising therapeutic target for cancer, with potential applications in modulating tumorigenic signaling pathways.
NAG-1/GDF15是一种肿瘤抑制因子，在结肠直肠癌（CRC）细胞中以前体形式合成，并经过切割产生其成熟形式。虽然前体NAG-1/GDF15的生物学功能尚不清楚，但我们的研究揭示了它在抑制致癌信号传导中的关键作用。我们证明，前体NAG-1/GDF15主要保留在细胞内，而其成熟形式则分泌到培养基中。NAG-1/GDF15或不可切割的R193A突变体的表达抑制β-连环蛋白和NF-κB信号传导，这是CRC进展中的关键途径。从机制上讲，前体NAG-1/GDF15与上皮细胞黏附分子（EpCAM）相互作用，阻止其切割和核转位，从而降低β-连环蛋白和NF-κB的活性。这种抑制作用与细胞周期蛋白D1和c-myc等致癌靶点的表达降低相关。在体内，NAG-1/GDF15的表达显著降低癌症异种移植模型中的肿瘤生长，同时伴有增殖减少和凋亡增加。此外，对公共数据集的分析表明，高NAG-1/GDF15表达与CRC患者生存率提高相关。这些发现突出了通过形成前体NAG-1/GDF15的NAG-1/GDF15作为一种有前景的癌症治疗靶点，在调节致瘤信号通路方面具有潜在应用价值。
