The 104-123 amino acid sequence of the β-domain of von Hippel-Lindau gene product is sufficient to inhibit renal tumor growth and invasion

Kaustubh Datta, C. Sundberg, S. A. Karumanchi, D. Mukhopadhyay

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

The von Hippel-Lindau (VHL) tumor suppressor gene is mutated in patients with VHL disease and in the majority of patients with sporadic renal cell carcinomas (RCCs). RCCs are dependent on insulin-like growth factor-I receptor-mediated signaling for tumor growth and invasion in vivo. Reintroduction of the VHL gene product (pVHL) can inhibit on insulin-like growth factor-I receptor-mediated signaling in RCC cells in vitro through interaction with protein kinase C δ and is mediated by a specific amino acid sequence (104-123) in the β-domain of the pVHL. In the present study, the amino acid sequence (104-123) of the pVHL was conjugated to the protein transduction domain of HIV-TAT protein (TATFLAGVHL-peptide) to facilitate entry into cells, and we demonstrate that this amino acid region of VHL is sufficient to block proliferation and invasion of 786-O renal cancer cells in vitro. Furthermore, daily i.p. injections with the TATFLAGVHL peptide retarded and, in some cases, caused partial regression of renal tumors that were implanted in the dorsal flank of nude mice. Treatment with this peptide also inhibits the invasiveness of renal tumors. A 56% decrease in the proliferative index in tumors treated with the TATFLAGVHL-peptide versus control-peptide-treated mice was observed. Taken together, these results show the novel importance of a 20-amino acid sequence of the β-domain of the VHL gene product capable of inhibiting tumor growth and invasion. These results lay the foundation for a unique approach toward treating RCCs using this small-molecular-weight peptide fused to the TAT-sequence, which may, in the future, be used alone or in conjunction with other therapies.

Original languageEnglish (US)
Pages (from-to)1768-1775
Number of pages8
JournalCancer Research
Volume61
Issue number5
StatePublished - Mar 1 2001

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Amino Acid Sequence
Renal Cell Carcinoma
Kidney
Peptides
Growth
Genes
Neoplasms
IGF Type 1 Receptor
Human Immunodeficiency Virus Proteins
von Hippel-Lindau Disease
Tumor Suppressor Genes
Nude Mice
Protein Kinase C
Molecular Weight
Amino Acids
Injections
Therapeutics
In Vitro Techniques

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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The 104-123 amino acid sequence of the β-domain of von Hippel-Lindau gene product is sufficient to inhibit renal tumor growth and invasion. / Datta, Kaustubh; Sundberg, C.; Karumanchi, S. A.; Mukhopadhyay, D.

In: Cancer Research, Vol. 61, No. 5, 01.03.2001, p. 1768-1775.

Research output: Contribution to journalArticle

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abstract = "The von Hippel-Lindau (VHL) tumor suppressor gene is mutated in patients with VHL disease and in the majority of patients with sporadic renal cell carcinomas (RCCs). RCCs are dependent on insulin-like growth factor-I receptor-mediated signaling for tumor growth and invasion in vivo. Reintroduction of the VHL gene product (pVHL) can inhibit on insulin-like growth factor-I receptor-mediated signaling in RCC cells in vitro through interaction with protein kinase C δ and is mediated by a specific amino acid sequence (104-123) in the β-domain of the pVHL. In the present study, the amino acid sequence (104-123) of the pVHL was conjugated to the protein transduction domain of HIV-TAT protein (TATFLAGVHL-peptide) to facilitate entry into cells, and we demonstrate that this amino acid region of VHL is sufficient to block proliferation and invasion of 786-O renal cancer cells in vitro. Furthermore, daily i.p. injections with the TATFLAGVHL peptide retarded and, in some cases, caused partial regression of renal tumors that were implanted in the dorsal flank of nude mice. Treatment with this peptide also inhibits the invasiveness of renal tumors. A 56{\%} decrease in the proliferative index in tumors treated with the TATFLAGVHL-peptide versus control-peptide-treated mice was observed. Taken together, these results show the novel importance of a 20-amino acid sequence of the β-domain of the VHL gene product capable of inhibiting tumor growth and invasion. These results lay the foundation for a unique approach toward treating RCCs using this small-molecular-weight peptide fused to the TAT-sequence, which may, in the future, be used alone or in conjunction with other therapies.",
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