C18-Ceramide in Head & Neck Cancer Growth and Therapy

描述（由申请人提供）：本提案旨在验证c18 -神经酰胺生成的重构介导致命自噬，随后导致线粒体功能障碍，抑制HNSCC肿瘤生长的总体假设。作为推论，用c18 -神经酰胺类似物治疗HNSCCs，如c18 -吡啶-神经酰胺（C18-Pyr-Cer），其增强lc3脂化和线粒体靶向，诱导自噬介导的肿瘤抑制的假设也将得到验证。为了验证这些新的假设，提出了三个具体目标：确定cers1生成的C18-（二氢）神经酰胺通过诱导自噬调控HNSCC生长抑制的作用。具体目标2。明确CerS1/ c18 -神经酰胺信号诱导致死自噬的下游机制。具体目标3。明确c18 -神经酰胺和LC3-II在选择性线粒体靶向自噬体以增强致死性自噬和肿瘤抑制中的作用。总的来说，本应用中提出的研究将有助于确定c18 -神经酰胺信号选择性调节致死性自噬的新机制，从而抑制HNSCC肿瘤的生长。

DESCRIPTION (provided by applicant): This proposal is designed to test the overall hypothesis that reconstitution of C18-ceramide generation mediates lethal autophagy, subsequently leading to mitochondrial dysfunction, and suppression of HNSCC tumor growth. As a corollary, the hypothesis that treatment of HNSCCs with C18-ceramide analogues, such as C18-pyridinium-ceramide (C18-Pyr-Cer), which enhance LC3-lipidation and mitochondrial targeting, induces autophagy-mediated tumor suppression will also be tested. To test these novel hypotheses, three Specific Aims are proposed: Specific Aim 1. Determine the roles of CerS1-generated C18-(dihydro)ceramide in the regulation of HNSCC growth inhibition via induction of autophagy. Specific Aim 2. Define the down-stream mechanisms by which CerS1/C18-ceramide signaling induces lethal autophagy. Specific Aim 3. Define the roles of C18-ceramide and LC3-II in selective mitochondrial targeting of autophagosomes to enhance lethal autophagy and tumor suppression. Collectively, studies proposed in this application will help define novel mechanisms involved selectively in the regulation of lethal autophagy by C18-ceramide signaling, which subsequently leads to suppression of HNSCC tumor growth. PUBLIC HEALTH RELEVANCE: Because novel strategies are needed for the treatment of human head and neck squamous cell carcinoma (HNSCC), the long-term objective of this proposal is to develop mechanism based therapeutic strategies for the treatment of this disease. To this end, these proposed studies will identify novel mechanisms by which C18- ceramide selectively induces lethal autophagy, leading to the suppression of HNSCC tumor growth. Data obtained from these studies will also help resolve the autophagy paradox, and define checkpoint mechanisms involved in inducing lethal versus survival autophagy by ceramide signaling, which will lead to the development of novel therapeutics against HNSCC.