Chen Ran, Jäättelä Marja, Liu Bin
Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
Cancers (Basel). 2020 Aug 27;12(9):2437. doi: 10.3390/cancers12092437.
Cancer cells generate large quantities of cytoplasmic protons as byproducts of aberrantly activated aerobic glycolysis and lactate fermentation. To avoid potentially detrimental acidification of the intracellular milieu, cancer cells activate multiple acid-removal pathways that promote cytosolic alkalization and extracellular acidification. Accumulating evidence suggests that in addition to the well-characterized ion pumps and exchangers in the plasma membrane, cancer cell lysosomes are also reprogrammed for this purpose. On the one hand, the increased expression and activity of the vacuolar-type H-ATPase (V-ATPase) on the lysosomal limiting membrane combined with the larger volume of the lysosomal compartment increases the lysosomal proton storage capacity substantially. On the other hand, enhanced lysosome exocytosis enables the efficient release of lysosomal protons to the extracellular space. Together, these two steps dynamically drive proton flow from the cytosol to extracellular space. In this perspective, we provide mechanistic insight into how lysosomes contribute to the rewiring of pH homeostasis in cancer cells.
癌细胞通过异常激活的有氧糖酵解和乳酸发酵产生大量细胞质质子作为副产物。为避免细胞内环境潜在的有害酸化，癌细胞激活多种酸清除途径，促进细胞质碱化和细胞外酸化。越来越多的证据表明，除了质膜中已被充分表征的离子泵和交换器外，癌细胞的溶酶体也为此目的进行了重新编程。一方面，溶酶体限制膜上液泡型H-ATP酶（V-ATP酶）表达和活性的增加，再加上溶酶体区室体积的增大，大大提高了溶酶体的质子储存能力。另一方面，增强的溶酶体胞吐作用使溶酶体质子能够有效地释放到细胞外空间。这两个步骤共同动态驱动质子从细胞质流向细胞外空间。从这个角度出发，我们深入探讨了溶酶体如何促进癌细胞pH稳态的重新调节。
