Rotin D, Steele-Norwood D, Grinstein S, Tannock I
Department of Medicine and Medical Biophysics, Ontario Cancer Institute, Toronto, Canada.
Cancer Res. 1989 Jan 1;49(1):205-11.
The Na+/H+ exchanger is involved in a variety of cellular processes, including regulation of intracellular pH and possibly the control of cell growth and proliferation. To study the role of the Na+/H+ exchanger in tumor growth, human sodium proton exchanger-deficient (HSPD) mutants were derived from the human bladder carcinoma cell line MGH-U1 (EJ) by the proton suicide selection technique (J. Pouyssegur et al., Proc. Natl. Acad. Sci. USA, 81: 4833-4837, 1984). The HSPD cells were approximately 40% larger and contained approximately 70% more DNA than the parental cells. They were unable to grow in vitro in the absence of bicarbonate at pH less than 7.0, whereas the parental cells grew well at pH greater than or equal to 6.6. This difference in acid sensitivity was abolished in the presence of bicarbonate. In contrast to the parental MGH-U1 cells, the Na+/H+-deficient HSPD cells either failed to grow tumors, or showed severely retarded tumor growth when implanted into immune-deprived mice. This difference in tumor growth was not attributed to differences in cell size and DNA content, because Na+/H+ exchange-competent large cells (HLC), derived during the same proton suicide selection process as the HSPD cells, grew tumors at a rate close to that of the parental cells. Cells derived from the few tumors which grew after implantation of HSPD mutant cells were revertants which had regained Na+/H+ activity. HSPD cells also failed to form spheroids in culture, and the only spheroid formed consisted of revertant cells which had regained both Na+/H+ exchange activity and tumorigenic capacity. These results suggest that the Na+/H+ exchanger is important for tumor growth.
钠氢交换体参与多种细胞过程，包括细胞内pH的调节以及可能对细胞生长和增殖的控制。为了研究钠氢交换体在肿瘤生长中的作用，通过质子自杀选择技术（J. Pouyssegur等人，《美国国家科学院院刊》，81: 4833 - 4837, 1984）从人膀胱癌细胞系MGH - U1（EJ）中获得了人钠质子交换缺陷（HSPD）突变体。HSPD细胞比亲代细胞大约大40%，DNA含量大约多70%。在pH小于7.0且无碳酸氢盐的情况下，它们无法在体外生长，而亲代细胞在pH大于或等于6.6时生长良好。在有碳酸氢盐存在的情况下，这种酸敏感性差异消失。与亲代MGH - U1细胞相比，缺乏钠氢交换能力的HSPD细胞植入免疫缺陷小鼠后，要么无法生长肿瘤，要么肿瘤生长严重受阻。肿瘤生长的这种差异并非归因于细胞大小和DNA含量的差异，因为在与HSPD细胞相同的质子自杀选择过程中获得的具有钠氢交换能力的大细胞（HLC），其肿瘤生长速度与亲代细胞接近。植入HSPD突变细胞后生长的少数肿瘤所衍生的细胞是恢复了钠氢交换活性的回复体。HSPD细胞在培养中也无法形成球体，唯一形成的球体由恢复了钠氢交换活性和致瘤能力的回复体细胞组成。这些结果表明钠氢交换体对肿瘤生长很重要。
