Redox Biology of Quiescent Normal Fibroblasts and Epithelial Cancer Progression

静止正常成纤维细胞的氧化还原生物学和上皮癌进展

• 批准号: 8677737
• 负责人: Prabhat C Goswami
• 金额: $ 20.2万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-19 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677737
• 关键词: 3' Untranslated Regions; Age; Aging; Antioxidants; Back; Biochemical; Bioinformatics; Biological Process; Biology; Cell Aging; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cells; Coculture Techniques; Conditioned Culture Media; Cyclin D1; Data; Development; Environment; Epithelial; Event; Excision; Fibroblasts; Flow Cytometry; G1 Phase; G2 Phase; Gene Expression; Gene Transfer; Human; Hydrogen Peroxide; Incidence; Injury; Knowledge; Life Style; Longevity; Malignant Neoplasms; Mammary gland; Manganese Superoxide Dismutase; Mediating; Messenger RNA; Metabolism; MicroRNAs; Mitochondria; Mitosis; Mitotic; Molecular; Nutritional; Oxidation-Reduction; Oxidative Stress; Phosphoric Monoester Hydrolases; Production; Proteins; RANTES; Reactive Oxygen Species; Regulatory Pathway; Research; S Phase; Sorting - Cell Movement; Telomerase; Telomere Shortening; Testing; Transcript; Untranslated Regions; adenoviral-mediated; age related; aged; anticancer research; base; cancer cell; cell growth; chemokine; healthy aging; innovation; novel; overexpression; research study; tumor progression

DESCRIPTION (provided by applicant): Cancer incidence increases exponentially with age, suggesting that a common mechanism contributes to both of these biological processes. One such mechanism is thought to be oxidative stress, due to an imbalance between the production of reactive oxygen species (ROS, e.g. O2.- and H2O2, arising from O2 metabolism), and their removal by the antioxidant network. A majority of aging-research is focused on understanding the mechanisms regulating replicative lifespan (Hayflick limit), which is attributed to telomere shortening and mitotic attrition. In the previous period of support (R01 CA111365), we discovered a novel mode of cellular aging (chronological lifespan), which is independent of both mitotic attrition and telomerase activity. We define chronological lifespan as the duration in which quiescent cells retain their capacity to re-enter the proliferative cycle and transit back to quiescence. Our data show that molecular and pharmacologically induced overexpression of manganese superoxide dismutase (MnSOD) suppresses age-associated increase in mitochondrial injury, and extends chronological lifespan. We also observed that MnSOD overexpression inhibits age-associated increases in the ability of quiescent fibroblasts to stimulate the proliferation of neighboring epithelial cancer cells. Finally, our recent preliminary results suggest that MnSOD-induced regulation of cell cycle regulatory pathways including the redox-sensitive phosphatase, DUSP1, and the chemokine, CCL5, could mediate chronological lifespan in human fibroblasts. These observations have now led us to test the specific hypothesis that MnSOD and ROS (O2.- and H2O2) regulate the chronological lifespan of human fibroblasts as well as their ability to influence the proliferation of epithelial cancer cells via edox-sensitive cell cycle regulatory pathways involving DUSP1 and CCL5. To investigate this hypothesis we will determine if: (a) MnSOD dependent expression of DUSP1 and CCL5 regulates the chronological lifespan of normal human fibroblasts; (b) cellular quiescence and redox-sensitive post-transcriptional mechanisms regulate MnSOD, DUSP1, and CCL5 expression; and (c) the aging of quiescent fibroblasts regulates the proliferation of epithelial cancer cells in co-cultures via the secretion of CCL5. A better understanding of the redox-biology of chronological lifespan and its effect on epithelial cancer progression will be of significance to aging and cancer research because this knowledge can greatly facilitate the development of novel nutritional and antioxidant-based approaches to promote healthy aging and suppress age-related cancer progression.

描述（由申请人提供）：癌症发病率随年龄呈指数增长，表明共同的机制有助于这两种生物学过程。一种这样的机制被认为是氧化应激，这是由于活性氧物质（ROS，例如O2-）的产生与氧化应激之间的不平衡。和H2 O2，由O2代谢产生），以及它们通过抗氧化剂网络的去除。大多数衰老研究都集中在了解调节复制寿命（海弗利克极限）的机制，这是由于端粒缩短和有丝分裂磨损。在前一阶段的支持（R 01 CA 111365），我们发现了一种新的细胞衰老模式（按时间顺序的寿命），这是独立的有丝分裂磨损和端粒酶活性。我们将按时间顺序的寿命定义为静止细胞保持其重新进入增殖周期并过渡回正常状态的能力的持续时间。 安静我们的数据表明，分子和锰超氧化物歧化酶（MnSOD）诱导的过表达抑制年龄相关的线粒体损伤的增加，并延长时间寿命。我们还观察到MnSOD过表达抑制了与年龄相关的静止成纤维细胞刺激邻近上皮癌细胞增殖的能力增加。最后，我们最近的初步 结果表明MnSOD诱导的细胞周期调节途径的调节，包括氧化还原敏感性磷酸酶DUSP 1和趋化因子CCL 5，可以介导人成纤维细胞的时间寿命。这些观察结果现在已经使我们测试了MnSOD和ROS（O2.和H2 O2）调节人成纤维细胞的按时间顺序的寿命以及它们通过涉及DUSP 1和CCL 5的氧化还原敏感性细胞周期调节途径影响上皮癌细胞增殖的能力。为了研究这一假设，我们将确定：（a）DUSP 1和CCL 5的MnSOD依赖性表达是否调节正常人成纤维细胞的时间寿命;（B）细胞静止和氧化还原敏感性转录后机制是否调节MnSOD、DUSP 1和CCL 5表达;以及（c）静止成纤维细胞的老化是否通过分泌CCL 5调节共培养物中上皮癌细胞的增殖。更好地了解时间寿命的氧化还原生物学及其对上皮癌进展的影响将对衰老和癌症研究具有重要意义，因为这些知识可以极大地促进新的营养和抗氧化剂为基础的方法的发展，以促进健康衰老和抑制与年龄相关的癌症进展。