Abstract
Extracts from the dried roots of gentian plant, Gentiana triflora, exhibit an antiproliferative activity against cultured and implanted tumor cells. However, the underlying mechanism has been unclear. In the present study, we show that the cell death induced by the extract occurs caspase-independently and depends on metabolic status of mitochondrial respiration. We observed that sensitivity to the extract was considerably lower in HeLa cells, which have a low rate of mitochondrial respiration, in comparison to Y3-Ag1.2.3 cells, which have a higher rate of respiration. Furthermore, sensitivity of HeLa cells to the extract increased significantly when they were forced to switch their energy dependency from glycolysis to mitochondrial respiration. These results indicate that the gentian extract targets on mitochondrial respira-tion. Consequently, different respiratory activities in mitochondria confer cells to have different suscepti-bilities to the extract-induced cell death.
Highlights
As a typical form of cell death, apoptosis has been extensively characterized
We show that the cell death induced by the extract occurs caspase-independently and depends on metabolic status of mitochondrial respiration
We observed that sensitivity to the extract was considerably lower in HeLa cells, which have a low rate of mitochondrial respiration, in comparison to Y3-Ag1.2.3 cells, which have a higher rate of respiration
Summary
As a typical form of cell death, apoptosis has been extensively characterized. reports concerning to additional types of cell death are accumulating, and the pathways for cell death are thought to be far more diverse than predicted [1,2,3]. Proliferative cancer cells derive most their energy from glycolysis rather than from mitochondrial respiration [13,14,15,16,17,18,19]. Those cancer cells are adapted for survival by using various pathways to avoid cell death [20,21]. A high concentration of glucose in culture strongly inhibits mitochondrial respiration in most cancer cells, a phenomenon called the Crabtree effect [23]. Those cells exhibit resistance to mitochondrial toxicants such as antimycin and oligomycin. Glycolysis and mitochondrial respiration are directly or indirectly involved in cell death and survival signaling
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