Wild-Type p53 Attenuates Cancer Cell Motility by Inducing Growth Differentiation Factor-15 Expression
Wild-Type p53 Attenuates Cancer Cell Motility by Inducing Growth Differentiation Factor-15 Expression
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DOI：
10.1210/en.2011-0059
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发表时间：
2011-08-01
期刊：
影响因子：
4.8
通讯作者：
Leung, Peter C. K.
中科院分区：
文献类型：
--
作者：
Cheng, Jung-Chien;Chang, Hsun-Ming;Leung, Peter C. K.
p53肿瘤抑制因子的主要功能是调节细胞周期和凋亡。除了其在恶性癌细胞中的功能外，p53还可以调节细胞迁移和侵袭，这有助于转移。生长分化因子-15（GDF-15）是TGF-β超家族的成员，已被证明是p53的下游靶点，与多种人类疾病和癌症进展相关。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。我们发现，野生型p53在两个高度侵袭性的p53无效的人类癌细胞系，SKOV 3和PC 3，衰减细胞迁移和运动通过基质胶。使用野生型p53和DNA结合缺陷型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。通过未涂覆的和Matrigel涂覆的transwell的细胞运动响应于用重组GDF-15处理而减少，而细胞增殖不受GDF-15处理的影响。此外，通过用GDF-15小干扰RNA处理，p53对GDF-15表达和分泌的诱导以及通过Matrigel的细胞运动的减少被减弱。本研究证实了p53通过GDF-15表达减弱癌细胞运动性的机制。此外，我们的研究结果表明，GDF-15介导的自分泌/旁分泌作用的p53的功能。（内分泌学152：2987-2995，2011）
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-beta 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. (Endocrinology 152: 2987-2995, 2011)