The Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA.
J Pathol. 2011 Apr;223(5):683-94. doi: 10.1002/path.2834. Epub 2011 Feb 21.
The PMEPA1 gene has been shown to suppress the androgen receptor (AR) and TGFβ signaling pathways and is abnormally expressed in prostate tumours. However, the role and mechanism action of PMEPA1 in AR-negative prostate cancer are unclear. Here, we demonstrate that inhibition of PMEPA1 suppresses AR-negative RWPE1 and PC-3 prostate cell proliferation through up-regulating the p21 transcription. Additionally, PMEPA1 overexpression suppresses the p21 expression and promotes cell proliferation. PMEPA1 is induced by TGFβ as a negative feedback loop to suppress Smad3 phosphorylation and nuclear translocation; up-regulates c-Myc; down-regulates p21; and promotes PC-3 cell proliferation. The PMEPA1 functions depend on its Smad2/3 binding motif. Consistently, depletion of Smad3/4, but not Smad2, blocks PMEPA1's functions of regulating c-Myc and p21. Importantly, stable depletion of PMEPA1 in PC-3 inhibits xenograft growth. Finally, we found that PMEPA1 is overexpressed in a subset of prostate cancer cell lines and tumours. These findings suggest that PMEPA1 may promote AR-negative prostate cancer cell proliferation through p21.
PMEPA1 基因已被证明能抑制雄激素受体 (AR) 和 TGFβ 信号通路，并在前列腺肿瘤中异常表达。然而，PMEPA1 在 AR 阴性前列腺癌中的作用和机制尚不清楚。在这里，我们证明抑制 PMEPA1 通过上调 p21 转录来抑制 AR 阴性 RWPE1 和 PC-3 前列腺细胞的增殖。此外，PMEPA1 的过表达抑制了 p21 的表达并促进了细胞增殖。PMEPA1 被 TGFβ 诱导作为负反馈环来抑制 Smad3 磷酸化和核转位；上调 c-Myc；下调 p21；并促进 PC-3 细胞增殖。PMEPA1 的功能取决于其 Smad2/3 结合基序。一致地，耗尽 Smad3/4，但不是 Smad2，阻断了 PMEPA1 调节 c-Myc 和 p21 的功能。重要的是，在 PC-3 中稳定耗尽 PMEPA1 抑制了异种移植物的生长。最后，我们发现 PMEPA1 在一部分前列腺癌细胞系和肿瘤中过表达。这些发现表明，PMEPA1 可能通过 p21 促进 AR 阴性前列腺癌细胞的增殖。
