The role of mitophagy in pancreatic cancer.

线粒体自噬在胰腺癌中的作用。

• 批准号: 433997649
• 负责人: Dr. Florian Scheufele
• 金额: --
• 依托单位: Cold Spring Harbor Laboratory
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/433997649?language=en
• 关键词: role; mitophagy; pancreatic; cancer.

Pancreatic cancer is currently ranked on fourth place of cancer related deaths. Although the prevalence of pancreatic cancer is still increasing and thus pancreatic cancer will reach rank two of cancer related deaths by the year 2030. Besides surgical resection of the tumor, which is essential for a curative treatment approach of pancreatic cancer, chemotherapy plays a central role. While chemotherapy was mainly used for treatment of locally irresectable and palliative cancer situations, today neoadjuvant treatment of locally advanced and also primary resectable pancreatic cancer gains more importance. Compared to conventional chemotherapy using gemcitabine, combination therapy with gemcitabine + nab-paclitaxel or the FOLFIRINOX regime showed promising results, with increased secondary resection rates and increased survival in locally advanced pancreatic cancer. Besides these achievements, in light of high sides effects and relative low rate of overall survival of established chemotherapy regimens, efforts have to be made to further improve therapy options for patients with pancreatic cancer. An important characteristic of cancer is its changed metabolism. Here, already Warburg and colleagues described a change in glucose metabolism away from oxidative phosphorylation and citric acid cycle to aerobe glycolysis. Furthermore, in pancreatic cancer, which nearly uniformly is associated with a mutation of the KRAS gene, changes in metabolism can be detected. In pancreatic cancer, there is a reduction of oxidative phosphorylation and citric acid cycle activity while glycolysis and activity the of the pentose phosphate pathway are increased. This results in reduced production of reactive oxygen species and an improved redox control of the cell, leading to increased cellular proliferation and progression of the tumor. For these changes in metabolism, mitophagy seems to play a pivotal role. Mitophagy is the targeted degradation of mitochondria by mechanisms of autophagy. By reduction of cellular mitochondrial content cancer cells adopt their metabolism leading to increased cellular proliferation and cancer progression. Recently a central regulator of mitophagy in KRAS mutated pancreatic cancer, namely the protein Nix, was identified. Nix is upregulated in pancreatic cancer and reduces cellular mitochondrial content by means of mitophagy. Inhibition of mitophagy in pancreatic cancer by targeting of Nix resulted in increased mitochondrial cellular content, reduced tumor proliferation and increased overall survival. The aim of the project is to further decipher the mechanisms of mitophagy and its impact on pancreatic cancer. This should built the basis for the development of new highly effective therapy options for patients with pancreatic cancer.

胰腺癌目前在癌症相关死亡人数中排名第四。虽然胰腺癌的发病率仍在上升，因此到2030年，胰腺癌将成为与癌症相关的死亡人数的第二位。除了手术切除肿瘤，这是胰腺癌根治性治疗的关键，化疗也发挥着核心作用。虽然化疗主要用于局部不能切除和姑息性癌症的治疗，但今天新辅助治疗对局部晚期和原发可切除的胰腺癌变得更加重要。与使用吉西他滨的常规化疗相比，吉西他滨+NaB-紫杉醇或FOLFIRINOX方案的联合治疗显示出有希望的结果，局部晚期胰腺癌的二次切除率和生存率都有所提高。除了这些成就外，鉴于现有化疗方案的副作用高和总体存活率相对较低，还必须努力进一步改善胰腺癌患者的治疗选择。癌症的一个重要特征是其新陈代谢的变化。在这里，Warburg和他的同事已经描述了葡萄糖代谢的变化，从氧化磷酸化和柠檬酸循环到好氧糖酵解。此外，在与KRAS基因突变几乎一致相关的胰腺癌中，可以检测到代谢的变化。在胰腺癌中，氧化磷酸化和柠檬酸循环活性降低，而糖酵解和磷酸戊糖途径的活性增加。这会减少活性氧的产生，改善细胞的氧化还原控制，从而增加细胞的增殖和肿瘤的进展。对于新陈代谢的这些变化，吞丝现象似乎起到了关键作用。有丝分裂吞噬是通过自噬机制使线粒体有针对性地降解。通过减少细胞线粒体的含量，癌细胞采用他们的新陈代谢，从而促进细胞增殖和癌症进展。最近，在KRAS突变的胰腺癌中发现了一种丝裂原吞噬的中央调节因子，即NIX蛋白。NIX在胰腺癌中上调，并通过有丝分裂减少细胞线粒体的含量。通过靶向Nix抑制胰腺癌中的有丝分裂，导致线粒体细胞含量增加，肿瘤增殖减少，总存活率增加。该项目的目的是进一步破译有丝分裂的机制及其对胰腺癌的影响。这应该为胰腺癌患者开发新的高效治疗方案奠定基础。