Chin L S, Murray S F, Zitnay K M, Rami B
Department of Neurosurgery, Program in Oncology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Clin Cancer Res. 1997 May;3(5):771-6.
Growth factors are known to regulate glioma proliferation. The glioma cell lines U87 and T98G were examined for evidence of an autocrine stimulatory loop involving the neurotrophin family of growth factors. Although neurotrophin-3 and TrkC RNA were detected by reverse transcription-PCR, there was no evidence of significant interaction between neurotrophin-3 and its cognate receptor TrkC. The microbial alkaloid K252a has been described to inhibit both Trk tyrosine kinase activity and neuroblastoma cell proliferation. K252a inhibited proliferation in U87 (IC50 = 1170 nM) and T98G (IC50 = 529 nM) but induced apoptosis in U87 cells only. At concentrations of 500 nM to 1 microM, K252a blocked only platelet-derived growth factor (PDGF)-mediated receptor autophosphorylation. These results suggest that an autocrine loop involving PDGF is functional and important for maintaining tumor growth. There is no evidence to support the existence of a neurotrophin-mediated autocrine loop. K252a, through inhibition of PDGF signal transduction, may be a novel therapeutic agent in the treatment of human gliomas.
已知生长因子可调节胶质瘤的增殖。对胶质瘤细胞系U87和T98G进行了检测，以寻找涉及神经营养因子家族生长因子的自分泌刺激环的证据。尽管通过逆转录聚合酶链反应检测到了神经营养因子-3和TrkC RNA，但没有证据表明神经营养因子-3与其同源受体TrkC之间存在显著相互作用。微生物生物碱K252a已被描述为可抑制Trk酪氨酸激酶活性和成神经细胞瘤细胞增殖。K252a抑制U87（IC50 = 1170 nM）和T98G（IC50 = 529 nM）的增殖，但仅诱导U87细胞凋亡。在500 nM至1 microM的浓度下，K252a仅阻断血小板衍生生长因子（PDGF）介导的受体自磷酸化。这些结果表明，涉及PDGF的自分泌环对于维持肿瘤生长具有功能性且很重要。没有证据支持神经营养因子介导的自分泌环的存在。K252a通过抑制PDGF信号转导，可能是治疗人类胶质瘤的一种新型治疗药物。
