Inhibition of human chorionic gonadotropin beta-subunit modulates the mitogenic effect of c-myc in human prostate cancer cells

Prostate. 2002 Nov 1;53(3):200-10. doi: 10.1002/pros.10151.

Abstract

Background: Amplification of the proto-oncogene c-myc has been identified as one of the most common genetic alterations in prostate cancer, thus making it an attractive therapeutic target. However, certain prostate cancer cells are unresponsive to c-Myc inhibition. The purpose of this study was to test the hypothesis that effective growth inhibition in the refractory cancer cells can be achieved by blocking c-myc along with a growth factor using a novel phosphorodiamidate morpholino antisense oligomer-based approach. Human chorionic gonadotropin, a growth factor implicated in neoplasm, causes activation of c-myc through a G-protein-coupled pathway of signal transduction.

Methods: In this study, the effect of inhibition of beta-hCG and c-myc singly or in combination was evaluated in DU145 (RB -/-, p53-/-, androgen-independent) and LNCaP (Rb+/+, p53 +/+, androgen-sensitive) human prostate cancer cell lines and in a DU145 subcutaneous xenograft murine model.

Results: Antisense phosphorodiamidate morpholino oligomers directed against beta-hCG and c-myc caused a specific decrease of the target protein levels. Unlike LNCaP cells, DU145 cell growth was refractory to c-Myc inhibition. Unresponsiveness to c-myc inhibition in DU145 cells was overcome by targeting both beta-hCG and c-myc genes, resulting in potentiation of the antiproliferative effect seen with inhibition of beta-hCG alone.

Conclusions: The inhibition of beta-hCG sensitizes prostate cancer cells to the antiproliferative effects of c-Myc inhibition, including tumors that are refractory to c-Myc decrease alone.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biological Availability
  • Chorionic Gonadotropin, beta Subunit, Human / antagonists & inhibitors*
  • Chorionic Gonadotropin, beta Subunit, Human / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Morpholines / pharmacology
  • Oligonucleotides, Antisense / genetics
  • Oligonucleotides, Antisense / pharmacology*
  • Phosphorus Compounds / pharmacology
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myc / biosynthesis
  • Proto-Oncogene Proteins c-myc / genetics
  • Random Allocation
  • Specific Pathogen-Free Organisms
  • Tumor Cells, Cultured

Substances

  • Chorionic Gonadotropin, beta Subunit, Human
  • Morpholines
  • Oligonucleotides, Antisense
  • Phosphorus Compounds
  • Proto-Oncogene Proteins c-myc
  • phosphorodiamidic acid