Intricate Interplay Between Androgen Receptor Signaling, Viral Infection and The Functionality of JAK/STAT and NF-kB Pathways

Introduction. In prostate cancer, tumor-promoting acquisition of androgen-independency may influence immunoediting via modulation of cell autonomous immune responses. Such responses, in which JAK/STAT/NF-kB signaling play central regulatory roles, concomitantly mediate the interaction of the cancer cell with the immune components of the microenvironment and determine its susceptibility to oncolytic viral infection. However, the mode, extent and consequence of crosstalk between androgen receptor (AR) signaling and inflammatory/antiviral responses is not known, and may determine the susceptibility of prostate cancer cells of different phenotype to oncolytic viruses.

Methods. Here, to dissect the mutual influence of AR signaling, antiviral responses and viral composition on oncolysis of prostate cancer cells we employed PC-3 metastatic prostate cancer cells subtypes that differ in AR expression, thus, mimicking the natural proses of prostate cell oncogenesis. Such cells, under different regimens of cytokine stimulation and/or activation state of AR and antiviral signaling pathways, were challenged with wild type and oncolytic Vesicular Stomatitis Virus (VSV) or with a novel oncolytic virus: the Epizootic hemorrhagic disease virus-Tel Aviv University (EHDV-TAU). Multiple parameters of infection, oncolysis, activation of signaling responses and regulation of gene were assessed.

Results. Overexpression of AR increased the constitutive expression of inflammation-related and interferon-stimulated genes (ISGs) in uninfected cells, indicative of crosstalk between AR and JAK/STAT/NF-kB pathways. Moreover, and in line with the increased ISGs expression levels, infection levels and signaling events that the infection evokes, were reduced in cells expressing higher levels of AR. Furthermore, and independently of AR expression status, while EHDV-TAU infection was markedly increased (as expected) by inhibition of JAK/STAT signaling, it was decreased upon NF-kB inhibition, revealing an unexpected dependency of virus replication on NF- kB signaling.

Conclusions and future directions. Intricate interplay between AR signaling, viral infection and the functionality of JAK/STAT and NF-kB pathways exist in prostate cancer cells. Consequences of such interactions should be taken into consideration while choosing virus-cell combinations and combination therapy settings.