Department of Obstetrics and Gynecology, Child and Family Research Institute, University of British Columbia, 4490 Oak Street, Vancouver, British Columbia, Canada, V6H 3V5.
Endocrinology. 2011 Aug;152(8):2987-95. doi: 10.1210/en.2011-0059. Epub 2011 May 17.
A major function of the p53 tumor suppressor is the regulation of the cell cycle and apoptosis. In addition to its well-documented functions in malignant cancer cells, p53 can also regulate cell migration and invasion, which contribute to metastasis. Growth differentiation factor-15 (GDF-15), a member of the TGF-β superfamily, has been shown to be a downstream target of p53 and is associated with diverse human diseases and cancer progression. In this study, we examined the potential role of GDF-15 in p53-regulated cancer cell motility. We show that overexpression of wild-type p53 in two highly invasive p53-null human cancer cell lines, SKOV3 and PC3, attenuated cell migration and the movement through Matrigel. Using wild-type p53 and DNA-binding-deficient p53 mutants, we found that the transcriptional activity of p53 is required in the induction of GDF-15 expression. Cell movement through uncoated and Matrigel-coated transwell decreased in response to treatment with recombinant GDF-15, whereas the cell proliferation was not affected by GDF-15 treatment. Moreover, the induction of GDF-15 expression and secretion by p53 and the reduction in cell movement through Matrigel were diminished by treatment with GDF-15 small interfering RNA. This study demonstrates a mechanism by which p53 attenuates cancer cell motility through GDF-15 expression. In addition, our results indicate that GDF-15 mediates the functions of p53 by autocrine/paracrine action.
p53 肿瘤抑制因子的一个主要功能是调节细胞周期和细胞凋亡。除了在恶性癌细胞中已有充分记载的功能外，p53 还可以调节细胞迁移和侵袭，从而促进转移。生长分化因子 15（GDF-15）是 TGF-β 超家族的成员之一，已被证明是 p53 的下游靶标，与多种人类疾病和癌症进展有关。在这项研究中，我们研究了 GDF-15 在 p53 调节的癌细胞运动中的潜在作用。我们表明，在两种高度侵袭性的 p53 缺失的人癌细胞系 SKOV3 和 PC3 中过表达野生型 p53，可减弱细胞迁移和穿过 Matrigel 的运动。使用野生型 p53 和 DNA 结合缺陷的 p53 突变体，我们发现 p53 的转录活性是诱导 GDF-15 表达所必需的。响应重组 GDF-15 的治疗，细胞穿过无涂层和 Matrigel 涂层的 Transwell 的运动减少，而细胞增殖不受 GDF-15 处理的影响。此外，p53 诱导的 GDF-15 表达和分泌以及穿过 Matrigel 的细胞运动减少，可被 GDF-15 小干扰 RNA 处理所消除。这项研究证明了 p53 通过 GDF-15 表达来减弱癌细胞运动的机制。此外，我们的结果表明，GDF-15 通过自分泌/旁分泌作用介导 p53 的功能。
