ANTISENSE INHIBITION OF THE PTI-1 ONCOGENE REVERSES CANCER PHENOTYPES

The genetic alterations and molecular events mediating human prostate cancer development and progression remain to be defined. Rapid express ion cloning and differential RNA display detect a putative oncogene, p rostate tumor-inducing gene 1 (PTI-1), that is differentially expresse d in human prostate (as well as breast, colon, and small cell lung) ca ncer cell lines, patient-derived prostate carcinomas, and blood from p atients with metastatic prostate cancer, PTI-1 consists of a unique 5' untranslated region (5' UTR) with significant sequence homology to My coplasma hyponeumoniae 23S ribosomal RNA juxtaposed to a sequence that encodes a truncated and mutated human elongation factor 1 alpha (Trun -EF), Stable expression of a nearly full-length 1.9-kb PTI-1 gene, but not the separate PTI-1 5' UTR or Trun-EF region, in normal rat embryo fibroblast cells, CREF-Trans 6, induces an aggressive tumorigenic phe notype in athymic nude mice, Blocking PTI-1 expression with antisense PTI-1 results in reversion of transformed PTI-1-expressing cells to a more normal cellular morphology with suppression in both anchorage-ind ependent growth and tumorigenic potential in athymic nude mice, These findings document that PTI-1 is indeed an oncogene, and directly block ing Pn-l expression can nullify cancer phenotypes. In these contexts, PTI-1 not only represents a gene with discriminating diagnostic proper ties but also may serve as a target for the gene-based therapy of huma n prostate and other cancers.