Single chain fragment anti-heparan sulfate antibody targets the polyamine transport system and attenuates polyamine-dependent cell proliferation.
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.
Welch
Johanna E
JE
Department of Clinical Sciences, Division of Oncology, Lund University, SE-22185, Lund, Sweden.
Bengtson
Per
P
Svensson
Katrin
K
Wittrup
Anders
A
Jenniskens
Guido J
GJ
Ten Dam
Gerdy B
GB
Van Kuppevelt
Toin H
TH
Belting
Mattias
M
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*
D015317:Biogenic Polyamines; D000518:Eflornithine; D006497:Heparan Sulfate; D007128:Immunoglobulin Fragments; C055966:immunoglobulin Fv