Androgen‐dependent Activation of Human Cytomegalovirus IE promoter in Prostate Cancer Cells.

Abstract

Human cytomegalovirus (HCMV) is a member of the herpesvirus family, which is sexually transmitted in adults. HCMV immediate early (IE) promoter is strongly activated by androgen agonist, R1881, in androgen‐dependent prostate cancer cells, LNCaP. However, IE promoter is not activated at all by R1881 in other cancer cells, which are forced to express AR. The activation of IE promoter by R1881 coincided with the changes of PKA activity and could be abbreviated by treatment with the inhibitor of PKA or the mutation of multiple copies of CRE. These results indicate that the activation of IE promoter by androgen results from the increase of PKA activities. Treatment with R1881 in LNCaP cells strongly suppressed the net production of prostaglandin E2, but enhanced the ability to activate PKA in response to PGE2 by expressing the EP4, the receptor for PGE2. This fact suggest the possibility that EP4 expression by androgen enables the cells to react to plentiful PGE2 derived from surrounding normal tissue, then activating PKA and IE promoter. The expression of catalytic beta II subunit of PKA by R1881 treatment, in a similar pattern to changes of IE promoter activities, suggest that the regulation of the expression of PKA catalytic beta II subunit might be direct upstream factor in IE promoter regulation. Taken together, present study demonstrated that HCMV IE promoter could be sustainedly activated in androgen‐dependent prostate cancer cells, which directs the expression of IE1/2 proteins containing oncogenic properties and proposed the possibility that HCMV be involved in oncogenesis in prostate.