Abstract
BackgroundCancer cell metabolism requires sustained pools of intracellular nicotinamide adenine dinucleotide (NAD+) which is maintained by a balance of NAD+ hydrolase activity and NAD+ salvage activity. We recently reported that human prostate cancer can be initiated following oncogene expression in progenitor-like luminal cells marked by low expression of the NAD+-consuming enzyme CD38. CD38 expression is reduced in prostate cancer compared to benign prostate, suggesting that tumor cells may reduce CD38 expression in order to enhance pools of NAD+. However, little is known about how CD38 expression is repressed in advanced prostate cancer and whether CD38 plays a role in regulating NAD+ levels in prostate epithelial cells.MethodsCD38 expression, its association with recurrence after prostatectomy for clinically localized prostate cancer, and DNA methylation of the CD38 promoter were evaluated in human prostate tissues representing various stages of disease progression. CD38 was inducibly over-expressed in benign and malignant human prostate cell lines in order to determine the effects on cell proliferation and levels of NAD+ and NADH. NAD+ and NADH were also measured in urogenital tissues from wild-type and CD38 knockout mice.ResultsCD38 mRNA expression was reduced in metastatic castration-resistant prostate cancer compared to localized prostate cancer. In a large cohort of men undergoing radical prostatectomy, CD38 protein expression was inversely correlated with recurrence. We identified methylation of the CD38 promoter in primary and metastatic prostate cancer. Over-expression of wild-type CD38, but not an NAD+ hydrolase-deficient mutant, depleted extracellular NAD+ levels in benign and malignant prostate cell lines. However, expression of CD38 did not significantly alter intracellular NAD+ levels in human prostate cell lines grown in vitro and in urogenital tissues isolated from wild-type and CD38 knockout mice.ConclusionsCD38 protein expression in prostate cancer is associated with risk of recurrence. Methylation results suggest that CD38 is epigenetically regulated in localized and metastatic prostate cancer tissues. Our study provides support for CD38 as a regulator of extracellular, but not intracellular, NAD+ in epithelial cells. These findings suggest that repression of CD38 by methylation may serve to increase the availability of extracellular NAD+ in prostate cancer tissues.
Highlights
Cancer cell metabolism requires sustained pools of intracellular nicotinamide adenine dinucleotide (NAD+) which is maintained by a balance of NAD+ hydrolase activity and NAD+ salvage activity
Several key questions remain unanswered, including (1) What is the level of CD38 expression in metastatic castration-resistant prostate cancer? (2) What mechanisms are responsible for low expression of CD38 in primary and metastatic prostate cancer? and (3) What are the functional consequences of CD38 expression in benign and malignant prostate epithelial cells? In this study, we address these questions using a range of approaches to evaluate prostate cancer tissues and cell lines
CD38 mRNA is reduced in metastatic castration-resistant prostate cancer We previously demonstrated that CD38 mRNA and protein expression is reduced in primary prostate cancer [7], but the expression of CD38 in metastatic prostate cancer is poorly defined
Summary
Cancer cell metabolism requires sustained pools of intracellular nicotinamide adenine dinucleotide (NAD+) which is maintained by a balance of NAD+ hydrolase activity and NAD+ salvage activity. We recently reported that human prostate cancer can be initiated following oncogene expression in progenitor-like luminal cells marked by low expression of the NAD+-consuming enzyme CD38. Most patients with advanced metastatic prostate cancer are treated with therapies targeting the androgen signaling axis, which can be initially effective but tumors eventually recur in a lethal castration-resistant state [2]. A key reason why advanced prostate cancer is so difficult to treat is that disease progression and treatment resistance is associated with epithelial plasticity [3, 4], loss of differentiated luminal epithelial features [5], and gain of a stem/progenitor-like transcriptional program [6,7,8]. Given that basal cells are CD38lo, we identified an inverse correlation between CD38 expression and progenitor activity
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