C18-Ceramide in Head & Neck Cancer Growth and Therapy

描述（由申请人提供）：本提案旨在检验C18-神经酰胺生成的重建介导致死性自噬，随后导致线粒体功能障碍和HNSCC肿瘤生长抑制的总体假设。作为推论，还将测试用C18-神经酰胺类似物如C18-吡啶鎓-神经酰胺（C18-Pyr-Cer）处理HNSCC诱导自噬介导的肿瘤抑制的假设，所述C18-神经酰胺类似物增强LC 3-脂化和线粒体靶向。为了验证这些新的假设，提出了三个具体目标：具体目标1。确定CerS 1产生的C18-（二氢）神经酰胺在通过诱导自噬调节HNSCC生长抑制中的作用。具体目标2。定义CerS 1/C18-神经酰胺信号传导诱导致死性自噬的下游机制。具体目标3。定义C18-神经酰胺和LC 3-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，本申请中提出的研究将有助于定义通过C18-神经酰胺信号传导选择性地参与调节致死性自噬的新机制，其随后导致HNSCC肿瘤生长的抑制。 公共卫生相关性：由于治疗人头颈部鳞状细胞癌（HNSCC）需要新的策略，因此本提案的长期目标是开发用于治疗该疾病的基于机制的治疗策略。为此，这些拟议的研究将确定C18-神经酰胺选择性诱导致死性自噬的新机制，从而抑制HNSCC肿瘤生长。从这些研究中获得的数据也将有助于解决自噬悖论，并定义通过神经酰胺信号传导诱导致死与存活自噬的检查点机制，这将导致开发针对HNSCC的新疗法。

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.