PDF(Pubmed)
Abstract：
Autophagy is a conserved catabolic process where double membrane-bound structures form around macromolecules or organelles targeted for degradation. Autophagosomes fuse with lysosomes to facilitate degradation and macromolecule recycling for homeostasis or growth in a cell autonomous manner. In cancer cells, autophagy is often up-regulated and helps cancer cells survive nutrient deprivation and stressful growth conditions. Here, we propose that the increased intracellular pH (pHi) common to cancer cells is sufficient to induce autophagic cell death. We previously developed tools to increase pHi in the Drosophila eye via overexpression of DNhe2, resulting in aberrant patterning and reduced tissue size. We examined fly eyes at earlier stages of development and found fewer interommatidial cells. We next tested whether this decrease in cell number was due to increased cell death. We found that the DNhe2-induced cell death was caspase independent, which is inconsistent with apoptosis. However, this cell death required autophagy genes, which supports autophagy as the mode of cell death. We also found that expression of molecular markers supports increased autophagy. Together, our findings suggest new roles for ion transport proteins in regulating conserved, critical developmental processes and provide evidence for new paradigms in growth control.
摘要：
自噬是一种保守的分解代谢过程,其中在靶向降解的大分子或细胞器周围形成双膜结合结构。自噬体与溶酶体融合以促进降解和大分子再循环，以细胞自主方式实现稳态或生长。在癌细胞中，自噬通常被上调，并帮助癌细胞在营养缺乏和应激生长条件下生存。这里,我们认为癌细胞常见的细胞内pH（pHi）增加足以诱导自噬性细胞死亡。我们先前开发了通过DNhe2的过表达来增加果蝇眼中的pHi的工具，从而导致异常的图案形成和组织大小减小。我们在发育的早期阶段检查了苍蝇的眼睛，发现了较少的雄间细胞。我们接下来测试这种细胞数量的减少是否是由于增加的细胞死亡。我们发现DNhe2诱导的细胞死亡是不依赖caspase的，这与细胞凋亡不一致。然而,这种细胞死亡需要自噬基因，它支持自噬作为细胞死亡的模式。我们还发现分子标记的表达支持自噬增加。一起,我们的研究结果表明离子转运蛋白在调节保守，关键的发育过程，并为生长控制的新范式提供证据。
