Essential and specific roles of Skp2 in Rb-deficiency induced tumorigenesis and hormone-sensitive prostate cancer cells
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Skp2 has been considered as an oncogene soon after its discovery since elevated Skp2 expression is often diagnosed in various human cancers. However, gain of function in mouse genetics studies suggested that over expression of Skp2 was not sufficient to induce tumorigenesis, so that ectopic Skp2 expression could be secondary effect of tumorigenesis. Here, we use the loss of function approaches to demonstrate that Skp2 plays important roles in tumorigenesis by a well-established Rb+/- mouse tumor model and in human prostate cancer cells.;The retinoblastoma protein Rb is a well known prototype tumor suppressor. Rb heterozygous mice develop pituitary intermediate lobe (IL) tumor with full penetrance after spontaneous loss of the remaining Rb allele, whereas in mouse embryos, homozygous Rb inactivation induces mid-gestation lethality. Here, we report that inactivation of Skp2 completely prevented tumorigenesis in Rb+/- mice, but paradoxically shortened survival of Rb -/- embryos. Unlike previously studied Rb targets, Skp2 inactivation did not mitigate deregulated proliferation and apoptosis in Rb1 deficient cells, but instead caused apoptotic ablation of the entire Rb-/- pituitary ILs and accelerated apoptosis in neuroepithelium of Rb-/- embryos. Rb deficient human retinoblastoma cells also underwent apoptosis after Skp2 knockdown. These results reveal that Skp2 becomes an essential survival gene when susceptible cells incur Rb deficiency.;Androgen androgen-receptor signaling in normal prostate epithelium promotes terminal luminal epithelial cell differentiation. In androgen sensitive prostate cancer cells, androgen-AR signaling gains the ability to promote both differentiation and proliferation. How the signaling promotes proliferation of androgen sensitive prostate cancer cells is important to understand the biology of and cure androgen sensitive prostate cancer. Herein, we identify an AR-Skp2 pathway in prostate cancer cells that depend on the AR for proliferation; in this pathway, AR is a robust upstream regulator of Skp2 through blocking the D-box-dependent degradation of this protein, and Skp2, in turn, serves as an essential downstream effector of AR in promoting proliferation independently of the differentiation-promoting function of AR. These results provide new knowledge on how AR functions in androgen-dependent prostate-cancer cells and identify strategies to specifically target the proliferation promoting function of AR without compromising cancer cell differentiation.
Source: Dissertation Abstracts International, Volume: 70-04, Section: B, page: 2025.;Advisors: Liang Zhu.