SUPPRESSION OF CAVEOLIN EXPRESSION INDUCES ANDROGEN SENSITIVITY IN METASTATIC ANDROGEN-INSENSITIVE MOUSE PROSTATE-CANCER CELLS

Although prostate cancer cells are often initially sensitive to androg en ablation, they eventually lose this response and continue to surviv e, grow and spread in the absence of androgenic steroids. The mechanis m(s) that underlie resistance to androgen ablation therapy remain most ly unknown. We have demonstrated that elevated caveolin protein levels are associated with human prostate cancer progression in pathological specimens(1). Here we show that suppression of caveolin expression by a stably transfected antisense caveolin-1 cDNA vector converted andro gen-insensitive metastatic mouse prostate cancer cells to an androgen- sensitive phenotype. Orthotopically grown tumors and low-density cell cultures derived from antisense caveolin clones had increased apoptosi s in the absence of androgenic steroids, whereas similarly grown tumor s and cells from vector (control) clones and parental cells were not s ensitive to androgens. Studies using a representative antisense caveol in clone showed that selection for androgen resistance in vivo correla ted with increased caveolin levels, and that adenovirus-mediated caveo lin expression blocked androgen sensitivity. Our results identify a ne w candidate gene for hormone-resistant prostate cancer in man and indi cate that androgen insensitivity can be an inherent property of metast atic prostate cancer.