Lucas C A, Gillies R J, Olson J E, Giuliano K A, Martinez R, Sneider J M
Department of Biochemistry, Colorado State University, Ft. Collins 80523.
J Cell Physiol. 1988 Jul;136(1):161-7. doi: 10.1002/jcp.1041360121.
One of the earliest events to occur upon the addition of serum to quiescent cells is an increase in the intracellular pH (pHin). The relationship between this pH change and proliferation is not known. In the present study, we investigate the consequences of acidifying the cytosol using the weak acid, 5', 5"-dimethyl oxazolidine 2,4-dione (DMO). At a concentration of 50 mM, DMO inhibits the serum-induced increases in pHin, DNA synthesis, and cell number. This concentration of DMO is shown not to inhibit the steady-state rate of mitochondrial respiration and not to inhibit DNA synthesis in a pH-independent fashion. The effects of DMO treatments are also shown to be reversible, indicating that this compound is not cytotoxic. These observations indicate that DMO inhibits cell proliferation by lowering intracellular pH. One important event that must occur prior to the initiation of DNA synthesis is an elevated rate of protein synthesis. The rate of protein synthesis in situ is extremely pH sensitive. Addition of 50 mM DMO to serum-stimulated cultures reduces the rate of leucine incorporation to unstimulated levels. These observations suggest that cytoplasmic acidification may inhibit proliferation through its effects on protein synthesis.
向静止细胞中添加血清后最早发生的事件之一是细胞内pH值（pHin）升高。这种pH变化与细胞增殖之间的关系尚不清楚。在本研究中，我们使用弱酸5'，5''-二甲基恶唑烷-2,4-二酮（DMO）研究细胞质酸化的后果。在浓度为50 mM时，DMO可抑制血清诱导的pHin升高、DNA合成和细胞数量增加。已表明该浓度的DMO不会抑制线粒体呼吸的稳态速率，也不会以pH非依赖性方式抑制DNA合成。DMO处理的效果也显示是可逆的，表明该化合物无细胞毒性。这些观察结果表明，DMO通过降低细胞内pH值来抑制细胞增殖。在DNA合成开始之前必须发生的一个重要事件是蛋白质合成速率升高。原位蛋白质合成速率对pH极为敏感。向血清刺激的培养物中添加50 mM DMO可将亮氨酸掺入率降低至未刺激水平。这些观察结果表明，细胞质酸化可能通过其对蛋白质合成的影响来抑制细胞增殖。
