The emergence of protocadherin-PC expression during the acquisition of apoptosis-resistance by prostate cancer cells

Oncogene. 2002 Nov 7;21(51):7861-71. doi: 10.1038/sj.onc.1205991.

Abstract

In order to identify gene products associated with the development of acquired therapeutic resistance by prostate cancer cells, we created two novel apoptosis-resistant prostate cancer cell lines, LNCaP-TR (phorbol-ester [TPA]-Resistant) and LNCaP-SSR (Serum Starvation-Resistant) by repeated transient exposure of cultured human LNCaP cells to apoptotic stimuli followed by expansion of surviving cell populations. These cell lines were found to be cross-resistant to the alternative selective agent and also hormone-resistant when xenografted into castrated male immunodeficient mice. RNA from the LNCaP-TR line was comparatively screened using a subtractive hybridization-PCR procedure. This allowed us to identify a 249 bp cDNA fragment that hybridized to a 4.8 kb mRNA preferentially expressed by the apoptosis-resistant cells. Using RACE procedures, we cloned and sequenced the complete 4.8 kb cDNA. It is an unusual member of the protocadherin gene family containing two large overlapping open reading frames encoding homologous polypeptides, one having a signal sequence and the other lacking a signal sequence and we refer to it as protocadherin-PC. LNCaP cells directly transformed with protocadherin-PC cDNA were comparatively resistant to phorbol-ester induced apoptosis. Antibody recognition studies demonstrating the cytoplasmic nature of the protcadherin-PC translation product and its propensity to bind beta-catenin suggest that it might influence the apoptotic sensitivity of prostate cancer cells through a unique mechanism.

Publication types

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

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Amino Acid Sequence
  • Androgens*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Base Sequence
  • Cadherins / biosynthesis
  • Cadherins / chemistry
  • Cadherins / genetics*
  • Cadherins / immunology
  • Cloning, Molecular
  • Culture Media, Serum-Free / pharmacology
  • Cytoplasm / metabolism
  • DNA, Complementary / genetics
  • Drug Resistance
  • Gene Amplification
  • Gene Expression Regulation, Neoplastic*
  • Genes
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Molecular Sequence Data
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / immunology
  • Neoplasm Transplantation
  • Neoplasms, Hormone-Dependent / genetics
  • Neoplasms, Hormone-Dependent / metabolism
  • Neoplasms, Hormone-Dependent / pathology*
  • Open Reading Frames
  • Peptides / chemistry
  • Peptides / genetics*
  • Peptides / immunology
  • Phenotype
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Protein Biosynthesis
  • Protein Sorting Signals / genetics
  • Subtraction Technique
  • Tetradecanoylphorbol Acetate / pharmacology

Substances

  • Androgens
  • Cadherins
  • Culture Media, Serum-Free
  • DNA, Complementary
  • Neoplasm Proteins
  • PCDH11Y protein, human
  • Peptides
  • Protein Sorting Signals
  • Tetradecanoylphorbol Acetate