文章：

溶酶体和自噬在细胞死亡控制中的作用

Lysosomes and autophagy in cell death control

原文发布日期：2005-10-01

DOI: 10.1038/nrc1738

类型: Review Article

开放获取: 否

要点：

1. Lysosomes contain catabolic hydrolases that participate in the digestion of autophagic material (after fusion between lysosomes and autophagosomes), in acute cell death (after lysosomal-membrane permeabilization, LMP) or in tissue invasion (after their release into the extracellular space).
2. LMP can be induced by classic apoptotic stimuli, intracellular second messengers such as reactive oxygen species and sphingosine, as well as by lysosomotropic toxins. Often, LMP causes mitochondrial outer-membrane permeabilization and caspase activation, which are two of the hallmarks of apoptosis.
3. Lysosomal alterations are common in cancer cells in which increased expression of lysosomal enzymes participates in tissue invasion and tumour growth, yet overexpressed heat-shock protein 70 (HSP70) locally prevents LMP. Targeting of lysosomes by lysosomotropic toxins, inhibitors of the vacuolar H⁺-ATPase or downmodulation/inhibition of HSP70 might have cancer-selective cytotoxic effects.
4. The autophagic sequestration of parts of the cytosol and/or cytoplasmic organelles is involved in the cellular adaptation to nutrient deprivation and sub-lethal damage. Therefore, autophagy might prevent cell death under some conditions. However, in some instances, particularly when apoptosis is inhibited, high levels of autophagy can function as a cell death effector mechanism.
5. Defective autophagy might participate in carcinogenesis, possibly owing to a reduced removal of defective organelles and/or damaged cells. Some chemotherapeutic agents can induce morphological changes, which indicate that autophagic cell death is occurring in the treated cells, but there is no formal proof that this type of cell death is involved in endogenous or therapeutic tumour suppression.
6. Specific therapeutic strategies might exploit the structural and functional abnormalities that affect the lysosomal and autophagic compartments in cancer cells.

要点翻译：

1. 溶酶体含有分解代谢水解酶，这些酶参与自噬物质的消化（在溶酶体与自噬体融合后）、急性细胞死亡（在溶酶体膜透化后）或组织侵袭（在酶释放到细胞外空间后）。
2. 溶酶体膜透化可由经典凋亡刺激、细胞内第二信使（如活性氧和鞘氨醇）以及亲溶酶体毒素诱导。通常，溶酶体膜透化会引起 mitochondrial 外膜透化和 caspase 激活，这两者是细胞凋亡的标志性特征。
3. 溶酶体改变在癌细胞中很常见，其中溶酶体酶表达增加参与组织侵袭和肿瘤生长，但过度表达的热休克蛋白70（HSP70）会局部阻止溶酶体膜透化。通过亲溶酶体毒素、液泡H+-ATP酶抑制剂靶向溶酶体，或下调/抑制HSP70，可能产生癌症选择性的细胞毒性效应。
4. 细胞质部分和/或细胞质细胞器的自噬性包裹参与细胞对营养剥夺和亚致死损伤的适应。因此，自噬在某些条件下可能防止细胞死亡。然而，在某些情况下，特别是在细胞凋亡被抑制时，高水平的自噬可作为细胞死亡的效应机制。
5. 自噬缺陷可能参与致癌作用，这可能是由于对有缺陷的细胞器和/或受损细胞的清除减少。一些化疗药物可诱导形态学变化，表明自噬性细胞死亡正在处理过的细胞中发生，但没有正式证据表明这种细胞死亡类型参与内源性或治疗性肿瘤抑制。
6. 特定的治疗策略可能利用影响癌细胞中溶酶体和自噬区室的结构和功能异常。

英文摘要：

Lysosomal hydrolases participate in the digestion of endocytosed and autophagocytosed material inside the lysosomal/autolysosomal compartment in acute cell death when released into the cytosol and in cancer progression following their release into the extracellular space. Lysosomal alterations are common in cancer cells. The increased expression and altered trafficking of lysosomal enzymes participates in tissue invasion, angiogenesis and sensitization to the lysosomal death pathway. But lysosomal heat-shock protein 70 locally prevents lysosomal-membrane permeabilization. Similarly, alterations in the autophagic compartment are linked to carcinogenesis and resistance to chemotherapy. Targeting these pathways might constitute a novel approach to cancer therapy.

摘要翻译： 

溶酶体水解酶在急性细胞死亡时释放到胞质中，可参与降解内吞和自噬的物质；当它们释放到细胞外空间时，还参与癌症进展。癌细胞中溶酶体常发生异常。溶酶体酶的表达升高及运输改变可促进组织侵袭、血管生成，并增强对溶酶体死亡通路的敏感性。然而，溶酶体热休克蛋白70可在局部阻止溶酶体膜通透性增加。同样，自噬区室的异常也与致癌及化疗耐药相关。靶向这些通路可能成为癌症治疗的新策略。

原文链接：

Lysosomes and autophagy in cell death control