奥沙利铂对结直肠癌（CRC）有效，但耐药性阻碍了治疗。我们发现奥沙利铂耐药 (OR) CRC 细胞系中的 Dickkopf-1（DKK1，一种分泌蛋白）上调，并且在大约 50% 的奥沙利铂耐药 CRC 肿瘤中 DKK1 水平增加了 2 倍以上。 DKK1 通过细胞骨架相关蛋白 4（CKAP4，一种 DKK1 受体）激活 AKT，在体外和体内调节奥沙利铂反应。 CKAP4 的亮氨酸拉链 (LZ) 结构域和分泌型 DKK1 的富含半胱氨酸结构域 1 (CRD1) 对于它们的相互作用和 AKT 信号转导至关重要。通过利用 LZ 蛋白，我们破坏了 DKK1 信号传导，增强了 OR CRC 细胞和异种移植肿瘤中的奥沙利​​铂敏感性。这表明 DKK1 通过 AKT 激活作为 CRC 中的化疗耐药因子。用 LZ 蛋白靶向 DKK1 为具有高 DKK1 水平的奥沙利铂耐药 CRC 提供了一种有前景的治疗策略。这项研究揭示了奥沙利铂耐药机制，并提出了应对这一挑战的创新干预措施。© 2024。作者。

Oxaliplatin is effective against colorectal cancer (CRC), but resistance hampers treatment. We found upregulated Dickkopf-1 (DKK1, a secreted protein) in oxaliplatin-resistant (OR) CRC cell lines and DKK1 levels increased by more than 2-fold in approximately 50% of oxaliplatin-resistant CRC tumors. DKK1 activates AKT via cytoskeleton-associated protein 4 (CKAP4, a DKK1 receptor), modulating oxaliplatin responses in vitro and in vivo. The leucine zipper (LZ) domain of CKAP4 and cysteine-rich domain 1 (CRD1) of secreted DKK1 are crucial for their interaction and AKT signaling. By utilizing the LZ protein, we disrupted DKK1 signaling, enhancing oxaliplatin sensitivity in OR CRC cells and xenograft tumors. This suggests that DKK1 as a chemoresistant factor in CRC via AKT activation. Targeting DKK1 with the LZ protein offers a promising therapeutic strategy for oxaliplatin-resistant CRC with high DKK1 levels. This study sheds light on oxaliplatin resistance mechanisms and proposes an innovative intervention for managing this challenge.© 2024. The Author(s).