Sausville E A, Moyer J D, Heikkila R, Neckers L M, Trepel J B
National Cancer Institute-Navy Medical Oncology Branch, Bethesda, Maryland 20814.
Ann N Y Acad Sci. 1988;547:310-21. doi: 10.1111/j.1749-6632.1988.tb23899.x.
Bombesin is a 14 amino acid peptide originally isolated from amphibian skin; its mammalian homolog is gastrin-releasing peptide (GRP). GRP is found in a high proportion of human small cell lung cancer (SCLC) cell lines. [Tyr4]bombesin caused an increase in intracellular Ca2+ ([Ca2+]i) in 5/11 SCLC cell lines tested. Bombesin action was not inhibited by agents known to alter the plasma membrane potential, nor did replacement of external Na+ with choline affect the bombesin-induced signal. [Tyr4]bombesin did not itself affect the membrane potential. Chelation of external Ca2+ reduced but did not prevent the bombesin-evoked increase in [Ca2+]i. This suggested that in SCLC, bombesin congeners not only promote an influx of extracellular Ca2+ but also release Ca2+ from intracellular stores. [Tyr4]bombesin increased levels of inositol 1,4,5-trisphosphate within seconds of addition to SCLC cell cultures and enhanced the accumulation of inositol 1-phosphate and inositol 4-phosphate in the presence of Li+. The SCLC cell lines responsive to bombesin constitutively expressed L-myc and did not express c-myc or N-myc. In contrast, SCLC cells non-responsive to bombesin had prominent constitutive expression of c-myc or N-myc with or without L-myc expression. Responding cell lines also had constitutive expression of the preproGRP gene, while non-responding cell lines showed no evidence of GRP gene expression. These data support the concept that SCLC which constitutively express the GRP gene and L-myc but not c-myc or N-myc can be stimulated in an autocrine fashion by GRP or its congeners to increase [Ca2+]i by a pathway involving phosphatidylinositol turnover.
蛙皮素是一种最初从两栖动物皮肤中分离出的含14个氨基酸的肽；其哺乳动物同源物是胃泌素释放肽（GRP）。GRP在高比例的人小细胞肺癌（SCLC）细胞系中被发现。[酪氨酸4]蛙皮素在5/11个受试的SCLC细胞系中引起细胞内钙离子浓度（[Ca2+]i）升高。蛙皮素的作用不受已知可改变质膜电位的试剂抑制，用胆碱替代细胞外钠离子也不影响蛙皮素诱导的信号。[酪氨酸4]蛙皮素本身不影响膜电位。螯合细胞外钙离子可降低但不能阻止蛙皮素引起的[Ca2+]i升高。这表明在SCLC中，蛙皮素类似物不仅促进细胞外钙离子内流，还从细胞内储存部位释放钙离子。[酪氨酸4]蛙皮素在加入SCLC细胞培养物后数秒内增加肌醇1,4,5 - 三磷酸水平，并在有锂离子存在时增强肌醇1 - 磷酸和肌醇4 - 磷酸的积累。对蛙皮素敏感的SCLC细胞系组成性表达L - myc，不表达c - myc或N - myc。相反，对蛙皮素不敏感的SCLC细胞有显著的c - myc或N - myc组成性表达，有或没有L - myc表达。有反应的细胞系也组成性表达前胃泌素释放肽原基因，而无反应的细胞系没有胃泌素释放肽基因表达的证据。这些数据支持这样的概念，即组成性表达胃泌素释放肽基因和L - myc但不表达c - myc或N - myc的SCLC可被胃泌素释放肽或其类似物以自分泌方式刺激，通过涉及磷脂酰肌醇代谢的途径增加[Ca2+]i。
