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Control of Apoptosis in Cancer by Survivin

Survivin 控制癌症细胞凋亡

基本信息

批准号：
9305689
负责人：
Dario C Altieri
金额：
$ 22.8万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9305689
关键词：
Actins Affect Apoptosis Basement membrane Bioenergetics Cancer Patient Cell Cycle Cell Polarity Cell Respiration Cessation of life Chemotaxis Clinic Competence Complex Cytoskeleton Data Disease Distant Drug resistance Energy-Generating Resources Exposure to Extracellular Matrix Focal Adhesions Follow-Up Studies Glycolysis Heterogeneity Homeostasis Impairment Invaded Kinetics Knowledge Malignant Neoplasms Malignant neoplasm of prostate Maps Membrane Metabolic Metabolism Mitochondria Modeling Movement Neoplasm Metastasis Oncogenes Organ Organelles Outcome Oxidative Phosphorylation Oxygen Parents Pathway interactions Peer Review Phosphorylation Phosphotransferases Play Process Proteolysis Publishing Quality Control Recruitment Activity Regulation Review Literature Role Shapes Signal Transduction Stimulus Stress Tissues Tumor Cell Invasion Tumor Cell Migration Warburg Effect Work cell motility cell transformation experimental study genome-wide in vivo metastatic process neoplastic cell new therapeutic target novel organelle movement parkin gene/protein prevent programs public health relevance receptor response small hairpin RNA spatiotemporal stemness survivin therapeutic target trafficking trait tumor tumor heterogeneity tumor metabolism tumorigenesis

项目摘要

PROJECT SUMMARY One of the hallmarks of cancer is the reprogramming of metabolism from oxidative phosphorylation that takes place in mitochondria to glycolysis, regardless of oxygen availability. This so-called “Warburg effect” is an important disease driver and hallmark of poor outcome. However, it is now clear that there is greater complexity in tumor metabolism, as mitochondria continue to play an important role in the bioenergetics of transformed cells, and fuel key cancer traits of proliferation, drug resistance, stemness and invasion. Work supported by CA78801 demonstrated that a pool of the cancer gene, survivin present in mitochondria of tumor cells maintained oxidative phosphorylation metabolism. In turn, energy produced via this pathway enabled the subcellular movement of mitochondria to the cortical cytoskeleton of tumor cells, fueling membrane lamellipodia dynamics, turnover of focal adhesion complexes, and sustained phosphorylation of cell motility kinases. Together, this led to heightened tumor chemotaxis, invasion and metastasis, in vivo. Published in the peer-reviewed literature (Sci Signal 8:389, 2015;; PNAS 112:8638, 2015), and discussed in three invited review articles (Pharmacol Rev 102:42, 2015;; Cell Cycle 14:20, 2015;; Clin Cancer Res 22:540, 2016), these results supported a model of spatiotemporal mitochondrial bioenergetics as a requirement of tumor cell motility, invasion and metastasis. In follow-up studies, we have now found that changes in mitochondrial size and shape, known as dynamics, as well as mechanisms of organelle quality control, such as mitophagy, are essential regulators of this pathway. Specifically, conditions that impair mitochondrial fusion, promote exaggerated mitochondrial fragmentation (fission), or activate mitophagy suppress mitochondrial trafficking and block tumor cell motility. Therefore, the hypothesis that organelle dynamics and quality control regulate spatiotemporal mitochondrial bioenergetics and metastatic competence can be formulated, and will constitute the focus of the present revision application. In continuity with the objectives of CA78810, the first specific aim will elucidate how mitochondrial fusion and fission regulate organelle movements, membrane-actin dynamics and the machinery of tumor cell motility. The second specific aim will focus on Parkin-dependent and – independent mitophagy, and a novel role of the FUNDC2 molecule as novel “metastasis suppressors”, regulating mitochondrial recruitment to the cortical cytoskeleton and the bioenergetics of tumor cell invasion. As dynamics and quality control are the primary effectors of mitochondrial heterogeneity, these studies are an ideal match to the objective of the PQ5 Program, will conclusively answer its overarching question of how does mitochondrial heterogeneity influence tumorigenesis or progression, and uncover actionable therapeutic targets to limit disease dissemination in the clinic.

项目摘要癌症的标志之一是氧化磷酸化代谢的重新编程，这种所谓的“瓦尔堡效应”是一种重要的疾病驱动因素和不良结局的标志。然而，现在很清楚，肿瘤代谢的复杂性，因为线粒体继续在肿瘤的生物能量学中发挥重要作用。转化的细胞，并燃料的增殖，耐药性，干细胞和入侵的关键癌症特征。工作由CA 78801支持的研究表明，肿瘤细胞线粒体中存在一个癌基因库，survivin，细胞维持氧化磷酸化代谢。反过来，通过这一途径产生的能量使细胞能够线粒体的亚细胞运动到肿瘤细胞的皮质细胞骨架，为膜提供燃料板状伪足动力学、粘着斑复合物的更新和细胞运动的持续磷酸化总之，这导致了体内肿瘤趋化性、侵袭和转移的增强。同行评审文献（Sci Signal 8：389，2015; PNAS 112：8638，2015），并在三个特邀综述中进行了讨论文章（Pharmacol Rev 102：42，2015; Cell Cycle 14：20，2015; Clinical Cancer Res 22：540，2016），这些结果支持时空线粒体生物能量学模型作为肿瘤细胞运动的要求，在后续的研究中，我们发现线粒体大小的变化和形状，称为动力学，以及细胞器质量控制机制，如线粒体自噬，特别是，损害线粒体融合的条件，过度的线粒体碎片化（分裂），或激活线粒体自噬抑制线粒体运输，阻断肿瘤细胞的运动。因此，假设细胞器动力学和质量控制调节时空线粒体生物能量学和转移能力可以被公式化，并将构成本修订申请的重点。与CA 78810的目标相延续，将阐明线粒体融合和分裂如何调节细胞器的运动，膜肌动蛋白动力学和肿瘤细胞运动机制。第二个具体目标将集中在帕金森病依赖性和- 独立的线粒体自噬，以及FUNDC 2分子作为新型“转移抑制因子”的新作用，调节线粒体向皮质细胞骨架的募集和肿瘤细胞侵袭的生物能量学。由于动力学和质量控制是线粒体异质性的主要影响因素，因此这些研究是一项重要的研究。与PQ 5计划目标的理想匹配，将最终回答其首要问题，即如何线粒体异质性影响肿瘤的发生或进展，并发现可行的治疗方法限制疾病在临床传播的目标。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Survivin in apoptosis control and cell cycle regulation in cancer.

DOI：
发表时间：
2003
期刊：
Progress in cell cycle research
影响因子：
0
作者：
D. Altieri
通讯作者：
D. Altieri

Profiles and legacies in cancer biology.

癌症生物学的概况和遗产。

DOI：
10.4161/cbt.3.5.811
发表时间：
2004
期刊：
Cancer biology & therapy
影响因子：
3.6
作者：
Altieri,DarioC
通讯作者：
Altieri,DarioC

Survivin as a global target of intrinsic tumor suppression networks.

DOI：
10.4161/cc.8.17.9457
发表时间：
2009-09-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
0
作者：
Guha M;Altieri DC
通讯作者：
Altieri DC

Survivin expression in mouse skin prevents papilloma regression and promotes chemical-induced tumor progression.

小鼠皮肤中生存素的表达可防止乳头状瘤消退并促进化学诱导的肿瘤进展。

DOI：
发表时间：
2003
期刊：
Cancer research.
影响因子：
0
作者：
Allen,SarahM;Florell,ScottR;Hanks,AdrianneN;Alexander,April;Diedrich,MiyoungJ;Altieri,DarioC;Grossman,Douglas
通讯作者：
Grossman,Douglas

Chk2 phosphorylation of survivin-DeltaEx3 contributes to a DNA damage-sensing checkpoint in cancer.

DOI：
10.1158/0008-5472.can-11-4035
发表时间：
2012-07-01
期刊：
Cancer research
影响因子：
11.2
作者：
Lopergolo A;Tavecchio M;Lisanti S;Ghosh JC;Dohi T;Faversani A;Vaira V;Bosari S;Tanigawa N;Delia D;Kossenkov AV;Showe LC;Altieri DC
通讯作者：
Altieri DC