Use of a truncated eif-5a1 polynucleotide to induce apoptosis in cancer cells

Abstract

The present invention relates to the combinatorial use of an siRNA targeted against an endogenous gene to knock out or knock down expression of the endogenous gene in a host and a delivery of a polynucleotide encoding the gene in a delivery vehicle/expression vector to the host to provide expression in the host of the protein encoded by the polynucleotide. The present invention also relates to a truncated form of eIF-5A1 that is useful for inducing apoptosis and killing of cells, especially cancer cells in a mammal.

1 - 57 . (canceled) 
     
     
         58 . An isolated eIF5A1 polypeptide consisting of (a) the amino acid sequence set forth in SEQ ID NO: 37 or (b) the amino acid sequence of amino acids 7-154 of SEQ ID NO: 35 except that the amino acid sequence of SEQ ID NO: 35 has at least one of the following mutations K50A, K50R, K67A, K47R, K67R, K50A/K67A, K50A/K47R, K50A/K67R, K50R/K67A, K50R/K47R, K50R/K67R, or K47A/K67A. 
     
     
         59 . A method for inducing apoptosis in a cancer cell or in a tumor in a subject, the method comprising administering the isolated polypeptide of  claim 58 . 
     
     
         60 . The method of  claim 58  further comprising administering a full length eIF5A1 polypeptide to the subject. 
     
     
         61 . The method of  claim 60  wherein the full length eIF5A1 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 35. 
     
     
         62 . The method of  claim 59  wherein the subject is a mammal. 
     
     
         63 . The method of  claim 62  wherein the mammal is a human. 
     
     
         64 . The method of  claim 59  wherein the induction of apoptosis slows cancer cell or tumor growth, arrests cancer cell or tumor cell growth, or kills cancer cells or reduces tumor size. 
     
     
         65 . The method of  claim 59  wherein the cancer is multiple myeloma. 
     
     
         66 . The method of  claim 60  further comprising an siRNA targeted against the 3′UTR of eIF5A1. 
     
     
         67 . The method of  claim 66  wherein the siRNA targets the sequence in eIF5A1 of 5′-GCT GGA CTC CTC CTA CAC A-3′ (SEQ ID NO: 45). 
     
     
         68 . The method of  claim 67  where in the siRNA is dsRNA and one strand of the dsRNA comprises the sequence of 5′-GCU GGA CUC CUC CUA CAC A-3′ (SEQ ID NO: 46). 
     
     
         69 . The method of  claim 67  wherein the siRNA is stabilized to prevent degradation in serum. 
     
     
         70 . The method of  claim 59  wherein the composition is administered intravenously, intraperitoneally or intratumorally.