Inducible silencing of protein kinase D3 inhibits secretion of tumor-promoting factors in prostate cancer.
Inducible silencing of protein kinase D3 inhibits secretion of tumor-promoting factors in prostate cancer.
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DOI：
10.1158/1535-7163.mct-11-0887
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发表时间：
2012-07
影响因子：
5.7
通讯作者：
Wang QJ
中科院分区：
文献类型：
--
作者：
LaValle CR;Zhang L;Xu S;Eiseman JL;Wang QJ
蛋白激酶D作为与癌症发展相关的几个信号通路的主要介导剂。异常PKD表达和活性已在多种癌症中得到证实，并且新型PKD抑制剂显示出有希望的抗癌活性。尽管有这些进展，PKD导致癌症发病的机制仍然未知。在这里，我们建立了一个新的作用PKD 3，PKD家族中研究最少的成员，在前列腺癌细胞的生长和运动，通过调节分泌的肿瘤促进因子的调节。使用稳定的诱导型敲低细胞模型和采用多种siRNA的瞬时敲低系统，我们证明内源性PKD 3的沉默显著降低前列腺癌细胞增殖、迁移和侵袭。此外，与来自对照细胞的条件培养基相比，来自PKD 3敲低细胞的条件培养基表现出较低的迁移潜力。进一步分析表明，PKD 3的消耗阻断了多种关键促肿瘤因子的分泌，包括MMP-9、IL-6、IL-8和GROα，但不改变这些因子的mRNA转录水平，这意味着分泌途径受损。更重要的是，皮下异种移植模型中PKD 3的诱导性消耗抑制了肿瘤生长并降低了小鼠肿瘤内GROα的水平。这些数据验证PKD 3作为前列腺癌中有前途的治疗靶点，并阐明了分泌的肿瘤促进因子在前列腺癌进展中的作用。
Protein kinase D acts as a major mediator of several signaling pathways related to cancer development. Aberrant PKD expression and activity have been demonstrated in multiple cancers, and novel PKD inhibitors show promising anti-cancer activities. Despite these advances, the mechanisms through which PKD contributes to the pathogenesis of cancer remain unknown. Here, we establish a novel role for PKD3, the least studied member of the PKD family, in the regulation of prostate cancer cell growth and motility through modulation of secreted tumor-promoting factors. Using both a stable inducible knockdown cell model and a transient knockdown system employing multiple siRNAs, we demonstrate that silencing of endogenous PKD3 significantly reduces prostate cancer cell proliferation, migration, and invasion. Additionally, conditioned medium from PKD3 knockdown cells exhibits less migratory potential compared to that from control cells. Further analysis indicated that depletion of PKD3 blocks secretion of multiple key tumor-promoting factors including MMP-9, IL-6, IL-8, and GROα, but does not alter mRNA transcript levels for these factors, implying impairment of the secretory pathway. More significantly, inducible depletion of PKD3 in a subcutaneous xenograft model suppresses tumor growth and decreases levels of intratumoral GROα in mice. These data validate PKD3 as a promising therapeutic target in prostate cancer and shed light on the role of secreted tumor-promoting factors in prostate cancer progression.