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内容記述 |
A major hallmark of apoptosis is normotonic shrinkage of cells. Here, we studied the relation between apoptotic cell shrinkage and apoptotic cell death. Induction of the apoptotic volume decrease (AVD) under normotonic conditions was found to be coupled to facilitation of the regulatory volume decrease (RVD), which is known to be attained by parallel operation of Cl<SUP>-</SUP> and K<SUP>+</SUP> channels, under hypotonic conditions. Both the AVD induction and the RVD facilitation were found to precede cytochrome c release, initiator caspase (-8, -9) activation, effector caspase (-3) activation, DNA laddering and ultrastructural alterations in four cell types (human lymphoid U937, epithelial HeLa, rat pheochromocytoma PC12 and mouse neuroblastoma X rat glioma hybrid NG108-15 cells) after apoptotic insults with two distinct apoptosis inducers. Also, the AVD was not prevented by a broad-spectrum caspase inhibitor. When the AVD induction and the RVD facilitation were prevented by blocking volume-regulatory Cl<SUP>-</SUP> or K<SUP>+</SUP> channels, these cells did not show succeeding apoptotic biochemical and morphological events and were rescued from death. Thus, it is concluded that the AVD, which is caused by disordered cell volume regulation, is an early prerequisite to apoptotic events leading to cell death. It was previously reported that hypertonic stress triggers apoptosis in cell types that lack the regulatory volume increase (RVI). In fact, in Na<SUP>+</SUP>/H<SUP>+</SUP> antiporter -deficient CCL39 cells, which were found to lack the RVI mechanism, hypertonic stimulation was found to induce persistent cell shrinkage without following volume recovery, and then lead to succeeding apoptotic events and cell death. When the RVI ability was conferred by transfection of the gene of NHE1 isoform of Na<SUP>+</SUP>/H<SUP>+</SUP> antiporter, this cell line failed to exhibit apoptosis under hypertonic stimulation. Taken together, it is concluded that disordered or altered cell volume regulation is a prerequisite to apoptosis. |
要旨・審査要旨 / Abstract, Screening Result (198.8 kB)
