Ceramide Signaling in the Regulation of Head & Neck Cancer Cell Death and Therapy

总结 人乳头瘤病毒（HPV）在头颈部鳞状细胞癌（HNSCC）中起主要作用 发病机制特别是，HPV（+）HNSCC患者对化疗反应更好，如顺铂 （CDDP），与HPV（-）HNSCC患者相比。然而，分子机制和信号通路 参与HPV介导的化学敏感性的基因在很大程度上是未知的。因此，本申请的总体目标是 确定HNSCC细胞对HPV感染的化学敏感性的机制， 神经酰胺代谢和信号传导。我们的治疗目标是利用这种机制信息， 开发新策略来增强化疗诱导的HNSCC细胞死亡和肿瘤抑制 没有HPV感染。基于我们新的和未发表的初步数据，我们提出了一个新的假设 HPV 16-E7增强CerS 1/C18-神经酰胺依赖性致死性线粒体自噬对化疗的反应- 诱导细胞应激信号传导，导致增强的HNSCC细胞死亡和肿瘤抑制。这 将在三个特定目的中检验假设：1）确定HPV 16-E6与HPV 16-E7在 神经酰胺介导的致死性线粒体自噬的调节; 2）确定HPV 16-E7 信号传导增强神经酰胺依赖性致死性线粒体自噬;和3）定义治疗作用， HPV 16-E7信号在神经酰胺依赖性致死性线粒体自噬和HNSCC中的调控机制 肿瘤抑制总的来说，这些研究将有助于开发基于机制的治疗策略， HPV 16-E7/C18-神经酰胺介导的致死性线粒体自噬信号通过增强肿瘤抑制作用 HNSCC患者的化疗。

SUMMARY Human papilloma virus (HPV) plays major roles in head and neck squamous cell carcinoma (HNSCC) pathogenesis. Paradoxically, HPV(+) HNSCC patients respond better to chemotherapy, such as cisplatin (CDDP), compared to HPV(-) HNSCC patients. However, molecular mechanisms and signaling pathways involved in HPV-mediated chemosensitivity are largely unknown. Thus, the overall goal of this application is to define the mechanisms involved in chemosensitivity of HNSCC cells in response to HPV infection with regard to ceramide metabolism and signaling. Our therapeutic goal is to utilize this mechanistic information for the development of novel strategies to enhance chemotherapy-induced HNSCC cell death and tumor suppression without HPV infection. Based on our novel and unpublished preliminary data, we propose a novel hypothesis that HPV16-E7 enhances CerS1/C18-ceramide-dependent lethal mitophagy in response to chemotherapy- induced cellular stress signaling, leading to enhanced HNSCC cell death and tumor suppression. This hypothesis will be tested in three Specific Aims: 1) Determine the roles of HPV16-E6 versus HPV16-E7 in the regulation of ceramide-mediated lethal mitophagy; 2) Determine the mechanisms by which HPV16-E7 signaling enhances ceramide-dependent lethal mitophagy; and 3) Define the therapeutic roles and mechanisms of HPV16-E7 signaling in the regulation of ceramide-dependent lethal mitophagy and HNSCC tumor suppression. Overall, these studies will help develop mechanism-based therapeutic strategies to induce HPV16-E7/C18-ceramide-mediated lethal mitophagy signaling for improving tumor suppression by chemotherapy in HNSCC patients.