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

The von Hippel-Lindau (VHL) tumor suppressor gene is mutated in patients wi th VHL disease and in the majority of patients with sporadic renal cell car cinomas (RCCs), RCCs are dependent on insulin-like growth factor-I receptor -mediated signaling for tumor growth and invasion in vivo. Reintroduction o f the VHL gene product (pVHL) can inhibit on insulin-like growth factor-I r eceptor-mediated signaling in RCC cells in vitro through interaction with p rotein kinase C delta and is mediated by a specific amino acid sequence (10 4-123) in the beta -domain of the pVHL, In the present study, the amino aci d sequence (104-123) of the pVHL was conjugated to the protein transduction domain of HIV-TAT protein (TATFLAGVHL-peptide) to facilitate entry into ce lls, 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, Fur thermore, daily i.p. injections with the TATFLAGVHL peptide retarded and, i n some cases, caused partial regression of renal tumors that were implanted in the dorsal flank of nude mice. Treatment with this peptide also inhibit s the invasiveness of renal tumors. A 56% decrease in the proliferative ind ex in tumors treated with the TATFLAGVHL-peptide versus control-peptide-tre ated mice was observed. Taken together, these results show the novel import ance of a 20-amino acid sequence of the beta -domain of the VHL gene produc t capable of inhibiting tumor growth and invasion, These results lay the fo undation for a unique approach toward treating RCCs using this small-molecu lar-weight peptide fused to the TAT-sequence, which may, in the future, be used alone or in conjunction with other therapies.