Antisense inhibition of the PTI-1 oncogene reverses cancer phenotypes

Antisense inhibition of the PTI-1 oncogene reverses cancer phenotypes

^*Departments of Pathology and Urology, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY 10032; and ^†GenQuest Incorporated, New York, NY 10032

Communicated by Allan H. Conney, Rutgers University, Piscataway, NJ (received for review July 16, 1997)

Abstract

The genetic alterations and molecular events mediating human prostate cancer development and progression remain to be defined. Rapid expression cloning and differential RNA display detect a putative oncogene, prostate tumor-inducing gene 1 (PTI-1), that is differentially expressed in human prostate (as well as breast, colon, and small cell lung) cancer cell lines, patient-derived prostate carcinomas, and blood from patients with metastatic prostate cancer. PTI-1 consists of a unique 5′ untranslated region (5′ UTR) with significant sequence homology to Mycoplasma hyopneumoniae 23S ribosomal RNA juxtaposed to a sequence that encodes a truncated and mutated human elongation factor 1α (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 phenotype 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-independent growth and tumorigenic potential in athymic nude mice. These findings document that PTI-1 is indeed an oncogene, and directly blocking PTI-1 expression can nullify cancer phenotypes. In these contexts, PTI-1 not only represents a gene with discriminating diagnostic properties but also may serve as a target for the gene-based therapy of human prostate and other cancers.

Footnotes

↵ ‡ To whom reprint requests should be sent at: Departments of Pathology and Urology, Columbia University College of Physicians and Surgeons, BB-1501, 630 West 168th Street, New York, NY 10032. e-mail: pbf1{at}columbia.edu.
ABBREVIATIONS:

PTI-1,

prostate tumor-inducing gene 1;

AS,

antisense;

S,

sense;

UTR,

untranslated region;

EF-1α,

elongation factor 1 α;

Trun-EF,

mutated and truncated EF-1α;

GAPDH,

glyceraldehyde-3-phosphate dehydrogenase