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Research Articles: Therapeutics, Targets, and Development

HIV-Tat protein transduction domain specifically attenuates growth of polyamine deprived tumor cells

¹ Sections of Glycobiology and ² Biogenic Amines, Department of Experimental Medical Research; and ³ Section of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden

Requests for reprints: Mattias Belting, Department of Clinical Sciences, Section of Oncology, Lund University, Barngatan 2:1, SE-221 85, Lund, Sweden. Phone: 46-46178549. E-mail: Mattias.Belting{at}med.lu.se

Abstract

Polyamines are essential for tumor cell growth, and the polyamine pathway represents an attractive target for cancer treatment. Several polyamine transport proteins have been cloned and characterized in bacteria and yeast cells; however, the mechanism of polyamine entry into mammalian cells remains poorly defined, although a role for proteoglycans has been suggested. Here, we show that the HIV-Tat transduction peptide, which is known to enter cells via a proteoglycan-dependent pathway, efficiently inhibits polyamine uptake. Polyamine uptake–deficient mutant cells with intact proteoglycan biosynthesis (CHO MGBG) displayed unperturbed HIV-Tat uptake activity compared with wild-type cells, supporting the notion that HIV-Tat peptide interferes with polyamine uptake via competition for proteoglycan binding sites rather than a putative downstream transporter. HIV-Tat specifically inhibited growth of human carcinoma cells made dependent on extracellular polyamines by treatment with the polyamine biosynthesis inhibitor -difluoromethylornithine; accordingly, the Tat peptide prevented intracellular accumulation of exogenous polyamines. Moreover, combined treatment with -difluoromethylornithine and HIV-Tat efficiently blocked tumor growth in an experimental mouse model. We conclude that HIV-Tat transduction domain and polyamines enter cells through a common pathway, which can be used to target polyamine-dependent tumor growth in the treatment of cancer. [Mol Cancer Ther 2007;6(2):782–8]

Grant support: Swedish Cancer Fund, Swedish Research Council, Swedish Foundation for Strategic Research (Forskarskolan för läkemedelsvetenskap [FLÄK]), Medical Faculty, Lund University (Avtal om läkarutbildning och forskning [ALF]), Association for International Cancer Research, Crafoordska Foundation, and Gunnar Nilsson Cancer Foundation (M. Belting).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: K. Mani and S. Sandgren contributed equally to this work.

⁴ K. Mani and M. Belting, unpublished observation.

Received 6/26/06; revised 11/16/06; accepted 12/21/06.