Heat shock protein 90 chaperone complex inhibitor enhanced radiosensitivity through modification of response to hormone and degradation of androgen receptor in hormone sensitive prostate cancer cell line

Abstract

Purpose/Objective: In hormone dependent prostate cancer, it is easily speculated that androgen or androgen deprivation affects proliferative activity or radiosensitivity, but there has been enough information how androgen or androgen deprivation influences the response to radiation. In this setting, the effect of dihydrotestosterone (DHT) on cellular growth and radiosensitivity was examined in hormone-sensitive human prostate cancer cell lines. LnCap. It has been shown that the binding of androgen receptor with heat shock protein 90 (Hsp90) plays an important role in stability of the receptor or hormone responsiveness, so that we focused Hsp90 chaperone complex inhibitor. In addition to the effect of DHT on radiosensitivity, it was examined how Hsp90 chaperone complex inhibitor modified the effect of DHT on radiosensitivity, and the underlining mechanisms were clarified. We focused on androgen receptor and its downstream signal transduction pathways because androgen receptor is a client protein of Hsp90. In addition to DHT, hydroxy-flutamide (OH-flutamide) was also used to confirm the effect of activation of androgen receptor and its downstream signal transduction pathway on radiosensitivity because androgen receptor of LnCap has a point mutation, leading to activation of androgen receptor caused by the binding of OH-flutamide. The results of this study would provide valuable information regarding the effect of androgen or modification of hormone responsiveness on radiosensitivity.