Inhibition of human chorionic gonadotropin beta-subunit modulates the mitogenic effect of c-myc in human prostate cancer cells.
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.
Devi
Gayathri R
GR
AVI BioPharma, Corvallis, Oregon 97333, USA. grdevi@avibio.com
Oldenkamp
Jennifer R
JR
London
Carla A
CA
Iversen
Patrick L
PL
D000818:Animals; D001682:Biological Availability; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D017553:Phosphorus Compounds / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D011897:Random Allocation; D013047:Specific Pathogen-Free Organisms; D014407:Tumor Cells, Cultured
D018997:Chorionic Gonadotropin, beta Subunit, Human; C000715470:MAS1 protein, human; D009025:Morpholines; D016376:Oligonucleotides, Antisense; D017553:Phosphorus Compounds; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; C436301:phosphorodiamidic acid