Lu Manman, Ren Yingli, Feng Sijia, Wang Shenggen, Xia Weiyue, Gu Baoru, Shen Yuhou, Yue Aimin, Li Na, Zhang Yongxi, Zhong Jiateng
Department of Oncology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.
Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.
Front Pharmacol. 2025 Apr 8;16:1508421. doi: 10.3389/fphar.2025.1508421. eCollection 2025.
Murine double minute 2 (MDM2), a key negative regulator of p53, forms a feedback loop with p53 to drive tumor progression, including colorectal cancer. Nutlin-3a, an MDM2 inhibitor, induces apoptosis in wild-type p53 tumors, but its effects on p53-mutated cancers and potential p53-independent apoptotic mechanisms remain unclear.
We investigated Nutlin-3a's effects on colon cancer cells with varying p53 phenotypes. Endoplasmic reticulum (ER) stress-associated CHOP was detected and knocked down to explore mechanisms. In vitro and in vivo experiments assessed Nutlin-3a's synergy with 5-fluorouracil and TRAIL.
Nutlin-3a activated caspase-8-dependent extrinsic apoptosis in colon cancer cells via DR5 upregulation, independent of p53 status. ER stress and CHOP activation mediated DR5 induction, driven by calcium release. Combined Nutlin-3a treatment enhanced sensitivity to 5-fluorouracil and TRAIL and through caspase-8 pathway activation.
These findings reveal a novel p53-independent apoptotic mechanism of Nutlin-3a involving ER stress and death receptor signaling. This pathway highlights Nutlin-3a's potential as an adjuvant therapy for colon cancer, even in p53-mutated tumors, by enhancing chemotherapeutic efficacy through extrinsic apoptosis.
小鼠双微体2（MDM2）是p53的关键负调控因子，与p53形成反馈回路以驱动肿瘤进展，包括结直肠癌。Nutlin-3a是一种MDM2抑制剂，可诱导野生型p53肿瘤细胞凋亡，但其对p53突变型癌症的影响以及潜在的不依赖p53的凋亡机制仍不清楚。
我们研究了Nutlin-3a对具有不同p53表型的结肠癌细胞的影响。检测并敲低内质网（ER）应激相关的CHOP以探索机制。体外和体内实验评估了Nutlin-3a与5-氟尿嘧啶和TRAIL的协同作用。
Nutlin-3a通过上调DR5在结肠癌细胞中激活caspase-8依赖性外源性凋亡，与p53状态无关。内质网应激和CHOP激活介导了由钙释放驱动的DR5诱导。联合使用Nutlin-3a治疗通过激活caspase-8途径增强了对5-氟尿嘧啶和TRAIL的敏感性。
这些发现揭示了Nutlin-3a一种新的不依赖p53的凋亡机制，涉及内质网应激和死亡受体信号传导。该途径突出了Nutlin-3a作为结肠癌辅助治疗的潜力，即使在p53突变的肿瘤中，通过外源性凋亡增强化疗疗效。
