Nkx3.1 and p27KIP1 Cooperate in Proliferation Inhibition and Apoptosis Induction in Human Androgen–Independent Prostate Cancer Cells

Prostate cancer (PC), which responds well to androgen ablation initially, invariably progresses to treatment resistance. The so-called androgen-independent PC is also a concern, since there is no effective therapy so far. Nkx3.1 is a putative prostate tumor suppressor that is expressed exclusively in the prostate under the regulation of androgen, and p27KIP1 functions as a cell proliferation inhibitor and apoptosis trigger by disrupting the cyclin-dependent kinase (CDK)-cyclin complex. Lack of expressions of Nkx3.1 and/or p27KIP1 have been detected in most advanced PC and is associated with poor clinical progression. Here, we show that endogenous expressions of both Nkx3.1 and p27KIP1 are lost in the androgen-independent PC3 PC cells, while remaining intact in LNCaP PC cells, which contain functional androgen receptor (AR) and are hormone-responsive. Ectopic restoration of either Nkx3.1 or p27KIP1 in PC3 cells results in reduced cell proliferation, and increased cell death. Both effects are synergisticall...