TITLE:
Development of a New Approach for the Therapy of Prostate Cancer with SPOP Mutations
AUTHORS:
David Lu, Jason J. Lee, Allen J. Lee, Ray M. Lee
KEYWORDS:
Prostate Cancer, SPOP, SRC-3, PRK-1, Lestaurtinib
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.6 No.10,
September
4,
2015
ABSTRACT: Advanced prostate cancer is treated with androgen deprivation, but most
patients eventually progress and need new therapy. Recent genomic/exomic
sequencing identified SPOP as the most frequently mutated gene in 6% - 15% of
prostate cancer. Based on the function of SPOP as a ubiquitin ligase in protein
degradation, it was hypothesized that loss-of-function mutations of SPOP led to
accumulation of SPOP substrates that enhance androgen receptor activity and
facilitate prostate cancer formation. SPOP
substrates could thus be potential targets for treatment of androgen-sensitive
prostate cancer. PubMed and BLAST search identified that Gli, SRC-3, and AWP1
are SPOP substrates, and that inhibition of PRK-1, a binding partner of AWP1,
by lestaurtinib suppressed androgen receptor activity. LNCaP, PC3, DU145 and
22RV1 prostate cancer cells were used to evaluate the effect of lestaurtinib.
LNCaP cells, an androgen-sensitive prostate cancer cell line, were the most
sensitive. SRC-3 protein decreased when LNCaP cells were treated with
lestaurtinib; whereas PRK-1 increased in nucleus after lestaurtinib treatment.
These data suggest that lestaurtinib modulates SRC-3 and PRK-1 to
induced cell death in androgen-sensitive prostate cancer, and could be a useful
agent for future development for prostate cancer with SPOP mutations.