Role of Autophagy in Cancer

自噬在癌症中的作用

• 批准号: 8256633
• 负责人: Eileen P. White
• 金额: $ 30.78万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256633
• 关键词: Aneuploidy; Apoptosis; Apoptotic; Autophagocytosis; Biochemical; Biological; Buffers; Catabolic Process; Cell Death; Cell Survival; Cell physiology; Cells; Chromosomal Instability; Chromosomes; Cytoplasm; DNA Damage; DNA strand break; Defect; Development; Eating; Endoplasmic Reticulum; Epithelial Cells; Event; Failure; Frequencies; Gene Amplification; Genes; Genome; Genome Stability; Genomic Instability; Growth; Health; Human; Inflammation; Life; Loss of Heterozygosity; Lysosomes; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Mammary gland; Measures; Mediating; Metabolic stress; Metabolism; Mitochondria; Mus; Mutation; Necrosis; Neurons; Nutrient; Oncogene Activation; Oncogenic; Organelles; Oxidative Stress; Pathway interactions; Play; Process; Production; Proteins; Quality Control; Reactive Oxygen Species; Recovery; Refractory Disease; Role; Solid Neoplasm; Source; Starvation; Stress; Suicide; Testing; Therapeutic; Tumor Suppression; base; cancer cell; cell type; comparative genomic hybridization; fitness; in vivo; kidney epithelial cell; malignant breast neoplasm; neoplastic cell; oxidative damage; prevent; response; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Autophagy is a catabolic process whereby cellular organelles and bulk cytoplasm are targeted for degradation in lysosomes. Recent evidence suggests that autophagy is a survival pathway necessary to sustain mammalian viability during periods of starvation, yet other evidence suggests that progressive autophagy can be a means to cell death if carried out to completion. Furthermore, constitutive autophagy is required to limit the accumulation of polyubiquitinated proteins in neuronal cells to prevent cellular degeneration. Thus autophagy is a homeostatic mechanism regulating the turnover of long-lived or damaged proteins and organelles that additionally functions to buffer metabolic stress during periods of nutrient limitation. Autophagy also plays a role in oncogenesis, although the mechanism is unknown. Allelic loss of the essential autophagy gene beclin1 is found with high frequency in human breast, ovarian and prostate cancers, and beclin1 mice are tumor prone, suggesting that autophagy is a tumor suppression mechanism. We have found that defects in apoptosis allow long-term cellular survival of immortal baby mouse kidney epithelial (iBMK) cells or mouse mammary epithelial cells (iMMECs) through autophagy. Moreover, autophagy localizes in tumors to regions of metabolic stress, and deficient autophagy compromises the survival to metabolic stress while promoting necrotic cell death, inflammation and tumor progression. These findings indicate, paradoxically, that loss of a survival pathway is oncogenic. While deficient autophagy reduces survival to starvation, this impaired cellular fitness is also associated with elevated DNA damage, gene amplification, chromosome gains and losses, and aneuploidy, suggesting that failure to maintain metabolism promotes genome instability. We thereby propose that autophagy functions to protect the genome, explaining the paradox: reduced cellular survival in autophagy defective cells is overcome by an increased mutation rate that drives tumor progression. We propose to determine how autophagy occurs, identify the mechanism of genome damage, and establish the role of chromosome instability caused by deficient autophagy in tumor progression. We specifically propose that autophagy is required to eliminate damaged proteins and organelles during metabolic stress, and failure to do so results in oxidative damage, mutations and tumor progression. PUBLIC HEALTH RELEVANCE: Determining how cancer cells defeat intrinsic suicide pathways and survive long periods of starvation only to resume growth and to progress to aggressive, treatment refractory disease is poorly understood. We have identified the catabolic, cellular "self eating" cannibalistic process of autophagy as a survival pathway utilized by solid tumor cells to survive starvation and protect their genome from mutations. We propose to establish the mechanism of autophagy and its consequence to cancer progression and therapeutic response.

描述（由申请人提供）：自噬是一种分解代谢过程，其中细胞器和大块细胞质在溶酶体中被降解。最近的证据表明，自噬是哺乳动物在饥饿期间维持生存能力所必需的一种生存途径，但其他证据表明，如果进行到完成，进行性自噬可能是细胞死亡的一种手段。此外，需要组成性自噬来限制神经元细胞中多泛素化蛋白的积累，以防止细胞变性。因此，自噬是一种调节长寿命或受损蛋白质和细胞器周转的稳态机制，在营养限制期间还具有缓冲代谢应激的功能。自噬也在肿瘤发生中起作用，尽管其机制尚不清楚。自噬必需基因beclin1等位基因丢失在人类乳腺癌、卵巢癌和前列腺癌中频率较高，beclin1小鼠易患肿瘤，提示自噬是一种肿瘤抑制机制。我们发现，凋亡缺陷允许不朽的幼鼠肾上皮细胞（iBMK）或小鼠乳腺上皮细胞（iMMECs）通过自噬长期存活。此外，自噬在肿瘤中定位于代谢应激区域，缺乏自噬损害代谢应激的生存，同时促进坏死细胞死亡、炎症和肿瘤进展。矛盾的是，这些发现表明，生存途径的缺失是致癌的。虽然缺乏自噬会降低饥饿存活率，但这种受损的细胞适应性也与DNA损伤升高、基因扩增、染色体获得和损失以及非整倍体有关，这表明无法维持代谢会促进基因组不稳定。因此，我们提出自噬功能保护基因组，解释了悖论：自噬缺陷细胞的细胞存活率降低是由驱动肿瘤进展的突变率增加所克服的。我们建议确定自噬是如何发生的，确定基因组损伤的机制，并确定由自噬缺陷引起的染色体不稳定在肿瘤进展中的作用。我们特别提出，在代谢应激过程中，自噬是消除受损蛋白质和细胞器所必需的，如果不这样做，就会导致氧化损伤、突变和肿瘤进展。公共卫生相关性：确定癌细胞如何击败内在的自杀途径，并在长时间的饥饿中存活下来，只是为了恢复生长并进展为侵袭性的，治疗难治性疾病，目前尚不清楚。我们已经确定了分解代谢，细胞“自噬”同类相食的自噬过程作为实体肿瘤细胞在饥饿中生存并保护其基因组免受突变的生存途径。我们建议建立自噬的机制及其对癌症进展和治疗反应的影响。