Suppression of Lung Cancer Growth by Ceramide

神经酰胺抑制肺癌生长

• 批准号: 8121463
• 负责人: Sahar Saddoughi
• 金额: $ 3.94万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121463
• 关键词: Air Pollution; Aromatic Polycyclic Hydrocarbons; Arsenic; Asbestos; Binding; Biological; Cancer Etiology; Carcinogens; Cause of Death; Cell Nucleus; Cells; Ceramides; Cessation of life; Chromates; Clinic; Complex; Data; Development; Disease; Environmental Risk Factor; Enzymes; Ethers; Exposure to; Generations; Growth; Human; In Vitro; Lead; Lung; Lung Neoplasms; Malignant neoplasm of lung; Mediating; Nickel; Nuclear; Nuclear Proteins; Oncogene Proteins; Patients; Protein Phosphatase 2A Regulatory Subunit PR53; Publishing; Radon; Regulation; Risk; Role; Signal Transduction; Smoking Status; Specificity; Sphingolipids; Sphingomyelinase; Testing; Therapeutic; United States; base; c-myc Genes; c-myc Proto-Oncogenes; cancer cell; cigarette smoking; defined contribution; design; dihydroceramide desaturase; improved; inhibitor/antagonist; novel; novel therapeutics; occupational hazard; protein phosphatase 2A inhibitor 2; public health relevance; restoration; smoke inhalation; statistics; success; treatment strategy; tumor growth

DESCRIPTION (provided by applicant): Exposure to cigarette smoke, air pollution and occupational hazards increases the risk of developing lung cancer. While the majority of these exposures are preventable, lung cancer causes the death of about 170,000 people a year in the United States, and overall survival statistics of patients with lung cancers have not been improved during the past several decades. Thus, there is a major need for the development of new therapeutic strategies against this disease. In our recent studies, ceramide, a bioactive sphingolipid, has been shown to exert anti-proliferative functions against lung cancers via degradation of the c-Myc proto-oncogene through directly binding to the inhibitor 2 of PP2A, (I2PP2A). However, mechanisms and biological roles by which ceramide-I2PP2A regulates c-Myc degradation remain unknown. This proposal is designed to examine the hypothesis that the direct interaction between ceramide and I2PP2A results in the restoration of nuclear PP2A activity leading to the degradation of c-Myc, and subsequently resulting in the suppression of lung tumor growth and/or progression. To test this hypothesis, two Specific Aims are proposed. In Specific Aim 1, it will be determined how ceramide-I2PP2A binding regulates the association between I2PP2A-PP2A leading to activation of nuclear PP2A. More specifically, it will be determined if the association between nuclear ceramide and I2PP2A causes changes in the association between I2PP2A and PP2A. Additionally the conformational/structural changes of I2PP2A-PP2A complex via ceramide-I2PP2A binding will be explored. The results of this first Aim will establish how the association between ceramide-I2PP2A regulates the interaction between I2PP2A-PP2A, resulting in enhanced activity of PP2A in human lung cancer cells. In Specific Aim 2, the mechanisms and biological roles of ceramide-I2PP2A binding on the regulation of c-Myc degradation via nuclear PP2A activation will be defined. More specifically, the contribution of endogenous ceramide generation in the nucleus by neutral sphingomyelinase 1 versus ceramide synthase 1 will be determined. Additionally, the signaling cascade causing c-Myc degradation via nuclear ceramide-I2PP2A binding, and subsequent activation of PP2A will be elucidated. Lastly, the biological roles of nuclear ceramide- I2PP2A binding in the suppression of lung tumor growth via regulation of PP2A dependent c-Myc degradation will be demonstrated. In summary, results of these Aims will define the structural, functional, and biological roles of ceramide-I2PP2A binding in the regulation of PP2A/c-Myc axis leading to the suppression of the growth and/or proliferation of human lung cancer cells. These studies will also lead to the development of mechanism-based therapeutic strategies, by specifically targeting oncoprotein I2PP2A and its downstream targets such as PP2A and c-Myc, through ceramide signaling for the treatment of human lung cancers. PUBLIC HEALTH RELEVANCE: Lung cancer is associated not only with smoking status, but also with exposure to environmental factors (smoke inhalation, combustion-generated carcinogens, air pollution) and/or occupational hazards (exposure to arsenic, asbestos, chromates, chloromethyl ethers, nickel, polycyclic aromatic hydrocarbons, radon). Regardless of the initiating factor, lung cancer remains to be the leading cause for cancer-related deaths in the United States, without much success for its therapeutic treatment in the clinic. Therefore, this proposal focuses on defining novel mechanisms by which bioactive sphingolipid ceramide mediates the suppression of lung cancer growth with the long-term objective to utilize these mechanistic data for the development of novel therapeutic strategies for the treatment of human lung cancers.

描述（由申请人提供）：暴露于香烟烟雾，空气污染和职业危害会增加患肺癌的风险。尽管这些暴露大多数是可以预防的，但在美国，肺癌每年导致每年约17万人死亡，并且在过去的几十年中，肺癌患者的总生存统计数据尚未得到改善。因此，主要需要开发针对这种疾病的新治疗策略。在我们最近的研究中，神经酰胺是一种生物活性鞘脂，已被证明通过通过直接与PP2A的抑制剂2结合（I2PP2A）来降解C-MYC原始癌细胞通过降解来对肺癌发挥抗增殖功能。然而，神经酰胺-I2PP2A调节C-MYC降解的机制和生物学作用尚不清楚。该提案旨在检验以下假设：神经酰胺与I2PP2A之间的直接相互作用导致核PP2A活性恢复导致C-MYC降解，并随后导致抑制肺部肿瘤生长和/或进展。为了检验这一假设，提出了两个具体目标。在特定的目标1中，将确定神经酰胺-I2pp2a的结合如何调节i2pp2a-ppp2a之间的关联导致核PP2A的激活。更具体地说，将确定核神经酰胺与I2PP2A之间的关联是否会导致I2PP2A和PP2A之间的关联发生变化。另外，将探讨I2PP2A-PP2A复合物通过神经酰胺-I2PP2A结合的构象/结构变化。第一个目标的结果将确定神经酰胺-I2PP2A之间的关联如何调节I2PP2A-PP2A之间的相互作用，从而导致PP2A在人肺癌细胞中的活性增强。在特定的目标2中，将定义神经酰胺-I2PP2A结合对通过核PP2A激活调节C-MYC降解的机制和生物学作用。更具体地说，将确定中性鞘磷脂酶1与神经酰胺合酶1在细胞核中产生内源性神经酰胺的贡献。此外，将阐明信号传导级联反应，从而导致C-Myc通过核神经酰胺-I2PP2A结合以及随后的PP2A激活。最后，将证明核神经酰胺-I2PP2A结合在抑制肺肿瘤生长中通过调节PP2A依赖C-MYC降解的生物学作用。总而言之，这些目标的结果将定义神经酰胺-I2pp2a在调节PP2A/C-MYC轴的调节中的结构，功能和生物学作用，从而导致抑制人类肺癌细胞的生长和/或增殖。这些研究还将通过专门针对癌蛋白I2PP2A及其下游靶标，例如PP2A和C-MYC，通过神经酰胺信号传导来治疗人类肺癌，从而导致基于机制的治疗策略的发展。 公共卫生相关性：肺癌不仅与吸烟状况有关，还与环境因素（吸入烟雾吸入，燃烧生成的致癌物，空气污染）和/或或/或职业危害（暴露于砷，石棉，铬酸盐，铬酸盐，氯甲基醚，镍甲基，镍，多余的水甲生酸酯，radon）。不管起始因素如何，在美国，肺癌仍然是与癌症相关死亡的主要原因，在诊所的治疗治疗方面没有太大的成功。因此，该提案的重点是定义新机制，通过这种机制，生物活性鞘脂神经酰胺介导了肺癌生长的抑制，其长期目标是利用这些机械数据来开发新的治疗策略来治疗人类肺癌。