http://dx.doi.org/10.18081/2333-5106/017-161-175
Jones Lorenzoni; Lutz Hartsell; Johnstone Rades
Abstract
Localized prostate cancer (PCa) has a high cure rate, but chemotherapy resistance is common in the hormone-refractory setting. The biological factor(s) for chemotherapy resistance in localized PCa is(are) not well understood. Notch 3 signaling contributes to stem-cell maintenance in neural prostates. It is not activated in the normal prostate epithelial cells but is linked to the progression of metastatic PCa. We screened 1,064 proteins for their cellular abundance changes in 10-fold enriched ALDH1-expressing prostate cancer stem cells (PCSC) from hormone-independent PCa xenografts (PC3), LAPC-4 castration-resistant xenografts, hormone-dependent LAPC-4 xenografts, radiation-selected DU145, or hormone-dependent LNCaP progenitor cell xenografts by the RAQ method and identified 50 overexpressed stem-cell-refractory therapy proteins. Notch 3 is inappropriately signaling in PCa, and diseases associated with gain-of-function Notch mutations (especially in Notch 3 genes) are proliferative and apoptotically resistant. Notch 3 is intrinsically upregulated in cancer stem cells with glycolytic metabolism. Both the membrane and soluble forms of Notch 3 are proposed as potential therapeutic targets. We later discovered that Notch 3 has stronger loss-of-function mutations in 58 localized PCa. The top 13 most frequent somatic mutations in PCa do not fall in these genes and total to 77% of all known PCa mutations. They overwhelmingly favor a system error; rather than a formula error, the purpose of the Human Genome Project (HGP) is to identify glitches in 4,000 common DNA repair genes.
Keywords: Prostate cancer; Notch 3; multivariate analysis; chemotherapy
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