Cytomegalovirus promotes proliferation and survival of prostate cancer cells and constitutes a therapeutic target

Abstract

Metastatic prostate cancer is incurable and new therapeutic targets and drugs are needed. Viruses are associated with several cancer types, but their connection to prostate cancer is unclear. Here we show that human herpes virus cytomegalovirus (CMV) infection is common in the healthy prostate epithelium as well as in prostate cancer, with 85% of tumors being infected to varying degrees. The CMV gene locusUL122-UL123upheld viral genome persistence in endogenously CMV infected prostate cancer cell lines. CMV promoted prostate cancer cell viability independently of androgen receptor status and anti-androgen resistance, partly through CMVUL97and the androgen signaling pathway. DNA intercalation mitigated CMV infection and reduced CMV-dependent tumor size in xenotransplantation experiments. The anti-herpes drug aciclovir showed modest effects, but the well tolerated CMV UL97 kinase inhibitor maribavir partly mimicked CMV loss by inducing apoptosis and attenuating proliferation, resulting in reduced tumor growthin vivo. We conclude that CMV infects prostate cellsin vivoand alters core prostate cancer cell properties, suggesting that it can be therapeutically targeted to improve prostate cancer outcomes.

The role of cytomegalovirus in prostate cancer incidence and mortality

“…Ethical permission for study of human samples was granted by the regional ethics committee of Sweden (2010/313-31/3). Prostate tissue and blood samples were collected from post-mortem donors between 2015 and 2020 through KI Donatum, Karolinska Institutet, Stockholm, Sweden, as described in 14 and 9 ; post-mortem cohort.…”

“…Tissues were processed and analyzed as described in 9 . Immunohistochemistry protocols and imaging are described in 9 .…”

“…Tissues were processed and analyzed as described in 9 . Immunohistochemistry protocols and imaging are described in 9 . This antibody was used: Cytomegalovirus pp71 (goat, 1:200, clone vC-20, sc-33323, polyclonal, Santa Cruz Biotechnology).…”

“…We recently reported that local CMV T-cell immunity in the prostate is associated with disease recurrence after radical prostatectomy in carriers of the common allele HLA-A*02-01 14 . Moreover, experimental CMV inhibition in models of prostate cancer can induce growth arrest and programmed cell death 9 .…”

“…In cells of the hematopoietic lineage, CMV is more abundant in CMV seropositive persons, although CMV often is present but at lower levels in individuals without an antibody response [27][28][29] . Large interindividual variation exists in abundance of CMV infected epithelial cells in the prostate, ranging from 0-100% 9 , raising the question whether CMV serostatus could also be a marker of CMV abundance in the prostate.…”