Welch Johanna E, Bengtson Per, Svensson Katrin, Wittrup Anders, Jenniskens Guido J, Ten Dam Gerdy B, Van Kuppevelt Toin H, Belting Mattias
Department of Clinical Sciences, Division of Oncology, Lund University, SE-22185, Lund, Sweden.
Int J Oncol. 2008 Apr;32(4):749-56.
The growth-promoting polyamines are polybasic compounds that efficiently enter cancer cells by as yet incompletely defined mechanisms. Strategies to inhibit their internalization may have important implications in the management of tumor disease. Here, we show that cellular binding and uptake of polyamines are inhibited by a single chain variable fragment anti-heparan sulfate (HS) antibody. Polyamine uptake was inhibited in a dose-dependent manner, and was associated with compensatory up-regulation of ornithine decarboxylase (ODC), i.e. the key enzyme of the polyamine biosynthesis pathway. Conversely, depletion of intracellular polyamines by the specific ODC-inhibitor alpha-difluoromethylornithine (DFMO) resulted in increased cellular binding of polyamine and anti-HS antibody. Importantly, anti-HS antibody also efficiently targeted DFMO-induced polyamine uptake, and combined polyamine biosynthesis inhibition by DFMO, and uptake inhibition by anti-HS antibody attenuated tumor cell proliferation in vitro. In conclusion, cell-surface HS proteoglycan is a relevant target for antibody-mediated inhibition of the uptake of polyamines, and polyamine-dependent cell proliferation.
促进生长的多胺是一类多元碱化合物，它们通过尚未完全明确的机制有效地进入癌细胞。抑制其内化的策略可能对肿瘤疾病的治疗具有重要意义。在此，我们表明，抗硫酸乙酰肝素（HS）单链可变片段抗体可抑制细胞对多胺的结合和摄取。多胺摄取呈剂量依赖性抑制，并与鸟氨酸脱羧酶（ODC）的代偿性上调有关，ODC是多胺生物合成途径的关键酶。相反，特定的ODC抑制剂α-二氟甲基鸟氨酸（DFMO）耗尽细胞内多胺会导致细胞对多胺和抗HS抗体的结合增加。重要的是，抗HS抗体也有效地靶向DFMO诱导的多胺摄取，并且DFMO联合抑制多胺生物合成以及抗HS抗体抑制摄取可在体外减弱肿瘤细胞增殖。总之，细胞表面HS蛋白聚糖是抗体介导抑制多胺摄取和多胺依赖性细胞增殖的相关靶点。
