Complement C1q activates tumor suppressor WWOX to induce apoptosis in prostate cancer cells.
Complement C1q activates tumor suppressor WWOX to induce apoptosis in prostate cancer cells.
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DOI：
10.1371/journal.pone.0005755
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发表时间：
2009-06-01
期刊：
影响因子：
3.7
通讯作者：
Chang NS
中科院分区：
文献类型：
--
作者：
Hong Q;Sze CI;Lin SR;Lee MH;He RY;Schultz L;Chang JY;Chen SJ;Boackle RJ;Hsu LJ;Chang NS
组织渗出液含有低水平的血清补体蛋白，其对前列腺癌进展的调节作用在很大程度上是未知的。我们检测了特定的血清补体成分在协调人前列腺DU 145细胞中肿瘤抑制因子p53和WWOX（也称为FOR或WOX 1）以及激酶ERK、JNK 1和STAT 3的活化中的作用。将DU 145细胞在1%正常人血清中或在去除指定补体蛋白的人血清中培养过夜。在无补体C1q或C6的条件下，WOX1和ERK主要存在于细胞质中而不磷酸化，而磷酸化的JNK1大量积累在细胞核中。外源性C1q迅速恢复WOX1激活（Tyr33磷酸化）在不到2小时。没有血清补体C9，p53被激活，和透明质酸（HA）逆转的效果。在无C6条件下，HA诱导转移增强子STAT3的活化。值得注意的是，外源性C1q显着诱导WOX1过表达DU145细胞的凋亡，但不是载体表达细胞。WOX1的显性失活和Y33R突变体阻断了凋亡作用。C1q不增强p53介导的凋亡。通过全内反射荧光（TIRF）显微镜，确定C1q通过部分分离和诱导形成簇状微绒毛以用于局部粘附（特别是在细胞之间）来使表达WOX 1的DU 145细胞的粘附不稳定。然后这些细胞经历收缩、膜起泡和死亡。值得注意的是，如通过免疫染色所确定的，与年龄匹配的正常前列腺组织相比，良性前列腺增生和前列腺癌显示出组织C1q的表达显著降低。我们的结论是，补体C1q可能通过激活WOX1和破坏细胞粘附诱导前列腺癌细胞凋亡。由于WOX1激活失败，C1q下调可增强前列腺增生和癌形成。
Tissue exudates contain low levels of serum complement proteins, and their regulatory effects on prostate cancer progression are largely unknown. We examined specific serum complement components in coordinating the activation of tumor suppressors p53 and WWOX (also named FOR or WOX1) and kinases ERK, JNK1 and STAT3 in human prostate DU145 cells. DU145 cells were cultured overnight in 1% normal human serum, or in human serum depleted of an indicated complement protein. Under complement C1q- or C6-free conditions, WOX1 and ERK were mainly present in the cytoplasm without phosphorylation, whereas phosphorylated JNK1 was greatly accumulated in the nuclei. Exogenous C1q rapidly restored the WOX1 activation (with Tyr33 phosphorylation) in less than 2 hr. Without serum complement C9, p53 became activated, and hyaluronan (HA) reversed the effect. Under C6-free conditions, HA induced activation of STAT3, an enhancer of metastasis. Notably, exogenous C1q significantly induced apoptosis of WOX1-overexpressing DU145 cells, but not vehicle-expressing cells. A dominant negative and Y33R mutant of WOX1 blocked the apoptotic effect. C1q did not enhance p53-mediated apoptosis. By total internal reflection fluorescence (TIRF) microscopy, it was determined that C1q destabilized adherence of WOX1-expressing DU145 cells by partial detaching and inducing formation of clustered microvilli for focal adhesion particularly in between cells. These cells then underwent shrinkage, membrane blebbing and death. Remarkably, as determined by immunostaining, benign prostatic hyperplasia and prostate cancer were shown to have a significantly reduced expression of tissue C1q, compared to age-matched normal prostate tissues. We conclude that complement C1q may induce apoptosis of prostate cancer cells by activating WOX1 and destabilizing cell adhesion. Downregulation of C1q enhances prostate hyperplasia and cancerous formation due to failure of WOX1 activation.
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