Viallet J, Sharoni Y, Frucht H, Jensen R T, Minna J D, Sausville E A
National Cancer Institute-Navy Medical Oncology Branch, Bethesda, Maryland.
J Clin Invest. 1990 Dec;86(6):1904-12. doi: 10.1172/JCI114923.
Cholera toxin (CT) inhibited the in vitro growth of three of four human small-cell lung carcinoma (SCLC) cell lines with a 50% inhibitory concentration of 27-242 ng/ml. Loss of surface membrane ruffling and the capacity of [Tyr4]-bombesin, vasopressin, and fetal calf serum to stimulate increases in intracellular free calcium clearly preceded effects on cellular metabolic activity and cell growth. 125I-[Tyr4]-bombesin binding was unaffected by CT treatment but [Tyr4]-bombesin stimulated phospholipase C activity was decreased in membranes from CT-treated SCLC cells. CT stimulated a rapid but transient increase in intracellular cyclic AMP ([cAMP]i) in SCLC. The effects of CT on susceptible SCLC were not reproduced by elevations of [cAMP]i induced by forskolin or cyclic AMP analogues. GM1 ganglioside, the cellular binding site for CT, was highly expressed in the CT-sensitive but not the CT-resistant SCLC cell lines. In contrast, expression of guanine nucleotide binding protein substrates for ADP-ribosylation by CT was similar. These data demonstrate the existence of a CT-sensitive growth inhibitory pathway in SCLC-bearing GM1 ganglioside. Addition of CT results in decreased responsiveness to several mitogenic stimuli. These results suggest novel therapeutic approaches to human SCLC.
霍乱毒素（CT）抑制了四种人小细胞肺癌（SCLC）细胞系中三种的体外生长，其50%抑制浓度为27 - 242 ng/ml。在对细胞代谢活性和细胞生长产生影响之前，细胞膜褶皱的丧失以及[酪氨酸4] - 蛙皮素、血管加压素和胎牛血清刺激细胞内游离钙增加的能力明显下降。125I - [酪氨酸4] - 蛙皮素结合不受CT处理的影响，但在经CT处理的SCLC细胞膜中，[酪氨酸4] - 蛙皮素刺激的磷脂酶C活性降低。CT刺激SCLC细胞内细胞内环磷酸腺苷（[cAMP]i）迅速但短暂地增加。福斯可林或环磷酸腺苷类似物诱导的[cAMP]i升高并未重现CT对敏感SCLC的影响。GM1神经节苷脂是CT的细胞结合位点，在CT敏感而非CT耐药的SCLC细胞系中高度表达。相比之下，CT用于ADP核糖基化的鸟嘌呤核苷酸结合蛋白底物的表达相似。这些数据表明在携带GM1神经节苷脂的SCLC中存在CT敏感的生长抑制途径。添加CT会导致对几种促有丝分裂刺激的反应性降低。这些结果提示了针对人SCLC的新治疗方法。
