Interactions Between IGFBP-3 and Nuclear Receptors in Prostate Cancer Apoptosis

摘要

IGFBP 3 is a potent inducer of apoptosis in both androgen-dependent and androgen-independent prostate cancer lines. When the nuclear receptor RXRalpha was described as an unexpected intracellular binding partner for IGFBP- 3 and effects on DNA transcription were demonstrated, rapid effects of IGFBP-3 on programmed cell death (apoptosis) still could not be explained These rapid effects on apoptosis were clarified when I hypothesized that IGFBP 3 was a biological signal for Nur77 nuclear receptor translocation to the mitochondria where an apoptotic cascade is initiated. We proposed to determine scientifically the protein regions in each of these important cell death molecules that essential for apoptotic action and demonstrate this observation with mouse models. Our data so far reveal a nuclear export sequence in IGFBP-3. Mutation of this sequence impairs its apoptotic activity. Utilizing the IGFBP 3 KO mouse, we show that IGFBP-3 s critical role in castration induced apoptosis. Mating studies are underway to determine the effects of genetically deleting Nur77 and IGFBP-3 in the ontogeny of prostate cancer.