Combination of fenretinide and ABT-263 induces apoptosis through NOXA for head and neck squamous cell carcinoma treatment

The overall survival for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) remains low, with little progress made over decades. Cisplatin, most frequently used for HNSCC treatment, activates mitochondria-dependent apoptosis through the BCL-2 family proteins. We have previously demonstrated that the pro-apoptotic BH3-only protein, NOXA plays a critical role in this process. NOXA binds and inactivates anti-apoptotic MCL-1, while the BCL-2 inhibitor ABT-263 is capable of inactivating anti-apoptotic BCL-2 and BCL-XL. We hypothesized that combination of NOXA and ABT-263 treatment increases cell death by simultaneously inhibiting anti-apoptotic BCL-2 family proteins in HNSCC cells. Here, we demonstrated that combination of ectopic NOXA expression and ABT-263 enhanced apoptosis in p53-inactive, p53 wild-type, and human papillomavirus (HPV)-positive HNSCC cell lines. Furthermore, a retinoid derivative and an endoplasmic reticulum stress inducer, fenretinide, induced NOXA, and combination of fenretinide and ABT-263 strongly induced apoptosis in HNSCC cells regardless of the HPV or p53 statuses. We also found that MCL-1 and BCL-XL are the primary targets of apoptosis induced by the combinations. These results will develop novel and alternative therapeutic strategies to directly modify the cell death machinery in HNSCC.复发或转移性头颈部鳞状细胞癌（head and neck squamous cell carcinoma, HNSCC）的总生存期仍处于较低水平，数十年来相关治疗领域未取得显著进展。顺铂是当前HNSCC临床应用最广泛的治疗药物，可通过BCL-2家族蛋白激活线粒体依赖性凋亡通路。我们既往研究已证实，促凋亡BH3-only蛋白NOXA在该过程中发挥关键作用：NOXA可结合并灭活抗凋亡蛋白MCL-1，而BCL-2抑制剂ABT-263能够同时灭活抗凋亡蛋白BCL-2与BCL-XL。我们提出假说：联合应用NOXA与ABT-263，可通过同时抑制HNSCC细胞内的抗凋亡BCL-2家族蛋白，从而增强细胞死亡效应。本研究证实，异位表达NOXA联合ABT-263处理，可在p53失活型、p53野生型以及人乳头瘤病毒（human papillomavirus, HPV）阳性的HNSCC细胞系中显著增强凋亡水平。进一步研究发现，类维生素A衍生物、内质网应激诱导剂芬维A胺（fenretinide）可诱导NOXA表达上调，且芬维A胺联合ABT-263能够在不依赖HPV或p53状态的HNSCC细胞中强力诱导凋亡。我们还发现，MCL-1与BCL-XL是上述联合疗法诱导凋亡的核心靶标。本研究结果有望开发出全新的替代性治疗策略，通过直接调控HNSCC的细胞死亡机制，为该病的临床治疗提供新方向。