title: Single chain fragment anti-heparan sulfate antibody targets the polyamine transport system and attenuates polyamine-dependent cell proliferation.
abstract: 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.
authors: Department of Clinical Sciences, Division of Oncology, Lund University, SE-22185, Lund, Sweden.
authors: Johanna E
authors: JE
authors: Welch
authors: Per
authors: P
authors: Bengtson
authors: Katrin
authors: K
authors: Svensson
authors: Anders
authors: A
authors: Wittrup
authors: Guido J
authors: GJ
authors: Jenniskens
authors: Gerdy B
authors: GB
authors: Ten Dam
authors: Toin H
authors: TH
authors: Van Kuppevelt
authors: Mattias
authors: M
authors: Belting
mesh_terms: D000818:Animals; D015317:Biogenic Polyamines / Q000037:antagonists & inhibitors* / Q000502:physiology; D001692:Biological Transport; D016466:CHO Cells; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D000518:Eflornithine / Q000494:pharmacology; D006367:HeLa Cells; D006497:Heparan Sulfate / Q000276:immunology*; D006801:Humans; D007128:Immunoglobulin Fragments / Q000494:pharmacology*
chemical_list: D015317:Biogenic Polyamines; D000518:Eflornithine; D006497:Heparan Sulfate; D007128:Immunoglobulin Fragments; C055966:immunoglobulin Fv