Cordyceps militaris Extract and the Main Component, Cordycepin, Modulate the Functions of Prostate Cancer Cells Partially Through the Adenosine A1 Receptor

Our previous study demonstrated that an extract of Cordyceps militaris (CM) derived from Samia Cynthia ricini inhibits testosterone-induced prostate hypertrophy in an animal model. However, the bioactive components in the CM extract that modulate the function of prostate cells have not been identified and characterized. To do this, the present study explored the effective component(s) from CM that influences the viability of androgen-responsive LNCaP prostate cancer cells and androgen-independent PC3 prostate cancer cells. Several fractions of CM, separated by gel filtration chromatography, decreased the viability and proliferation of both types of prostate cancer cells in either the presence or absence of testosterone propionate (TP). The fractions reduced TP-induced expression of the androgen-regulated genes FKBP5, TMPRSS2, and KLK3. NMR identified cordycepin, adenosine, and uridine as the active components in the CM fractions. The proliferation of LNCaP cells was inhibited by cordycepin, but not by either adenosine or uridine. Cordycepin, adenosine, and uridine reduced TP-mediated increases in FKBP5 and TMPRSS2 expression, and TP-mediated phosphorylation of the androgen receptor. Specific adenosine A1, A2, and A3 receptor antagonists did not block the inhibitory effects of cordycepin on cell proliferation, whereas the A1 receptor antagonist CPDPX (8-cyclopentyl-1,3-dipropylxanthine) reversed cordycepin-mediated inhibition of FKBP5 and TMPRSS2 expression. Thus, cordycepin exhibited both adenosine receptor–independent and adenosine A1 receptor–dependent effects. These findings suggest that cordycepin inhibits the proliferation of prostate cells independently of adenosine receptors, and that its modulatory effect on androgen-regulated gene expression is mediated through the adenosine A1 receptor.