The role of mitophagy in pancreatic cancer.

胰腺癌目前排在癌症相关死亡的第四位。尽管胰腺癌的患病率仍在增加，因此到2030年胰腺癌将达到癌症相关死亡的第二位。除了对胰腺癌的治愈性治疗方法至关重要的肿瘤手术切除外，化疗起着核心作用。虽然化疗主要用于治疗局部不可切除和姑息性癌症情况，但今天局部晚期和原发性可切除胰腺癌的新辅助治疗变得更加重要。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，增加了局部晚期胰腺癌的二次切除率和生存率。除了这些成就之外，鉴于现有化疗方案的高副作用和相对较低的总生存率，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它的代谢改变。在这里，瓦尔堡和他的同事已经描述了葡萄糖代谢从氧化磷酸化和柠檬酸循环到需氧菌糖酵解的变化。此外，在几乎一致地与KRAS基因突变相关的胰腺癌中，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，而糖酵解和戊糖磷酸途径的活性增加。这导致活性氧的产生减少和细胞的氧化还原控制改善，导致细胞增殖和肿瘤进展增加。对于这些代谢变化，线粒体自噬似乎起着关键作用。线粒体自噬是通过自噬机制靶向降解线粒体。通过减少细胞线粒体含量，癌细胞采用它们的代谢，导致细胞增殖增加和癌症进展。最近，KRAS突变胰腺癌中线粒体自噬的中心调节因子，即蛋白Nix，被鉴定。Nix在胰腺癌中上调，并通过线粒体自噬减少细胞线粒体含量。通过靶向Nix抑制胰腺癌中的线粒体自噬导致线粒体细胞含量增加、肿瘤增殖减少和总生存期增加。该项目的目的是进一步破译线粒体自噬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。

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.