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-1 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 delta and is mediated by a specific amino acid sequence (104-123) in the beta-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 beta-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.