Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
J Cell Physiol. 2010 Jun;223(3):623-9. doi: 10.1002/jcp.22058.
Profilin-1 (Pfn1), a ubiquitously expressed actin-binding protein, has gained interest in epithelial-derived cancer because of its downregulation in expression in various adenocarcinoma. Pfn1 overexpression impairs tumorigenic ability of human breast cancer xenografts thus suggesting that Pfn1 could be a tumor-suppressor protein. The objective of the present study was to determine how Pfn1 overexpression affects cell-cycle progression of breast cancer cells. We show that Pfn1 overexpression in MDA-MB-231 breast cancer cells causes cell-cycle arrest in G1 phase and dramatically reduced proliferation in culture. Pfn1 overexpression results in increased protein stability of p27(kip1) (p27-a major cyclin-dependent kinase inhibitor) and marked elevation in the overall cellular level of p27. Proliferation defect of Pfn1 overexpressers can be partly rescued by silencing p27 expression thus suggesting a critical role of p27 in Pfn1-induced growth inhibition of MDA-MB-231 cells. Finally, Pfn1 overexpression was found to sensitize MDA-MB-231 cells to apoptosis in response to cytotoxic stimulus thus suggesting for the first time that survival of breast cancer cells can also be negatively influenced by Pfn1 upregulation. These findings may provide novel insights underlying Pfn1's tumor-suppressive action.
肌动蛋白结合蛋白 Profilin-1（Pfn1）在各种腺癌中表达下调，因此引起了人们对其在源自上皮的癌症中的研究兴趣。Pfn1 的过表达会损害人乳腺癌异种移植物的致瘤能力，这表明 Pfn1 可能是一种肿瘤抑制蛋白。本研究的目的是确定 Pfn1 的过表达如何影响乳腺癌细胞的细胞周期进程。我们发现，Pfn1 在 MDA-MB-231 乳腺癌细胞中的过表达会导致细胞周期在 G1 期停滞，并显著降低细胞在培养中的增殖。Pfn1 的过表达导致 p27(kip1)（p27-一种主要的细胞周期蛋白依赖性激酶抑制剂）的蛋白稳定性增加，并且 p27 的整体细胞水平显著升高。沉默 p27 的表达可以部分挽救 Pfn1 过表达细胞的增殖缺陷，这表明 p27 在 Pfn1 诱导的 MDA-MB-231 细胞生长抑制中起关键作用。最后，发现 Pfn1 的过表达使 MDA-MB-231 细胞对细胞毒性刺激更敏感，从而引发细胞凋亡，这首次表明乳腺癌细胞的存活也可以受到 Pfn1 上调的负面影响。这些发现可能为 Pfn1 的肿瘤抑制作用提供新的见解。
