Platelet factor 4 induces cell apoptosis by inhibition of STAT3 via up-regulation of SOCS3 expression in multiple myeloma
Platelet factor 4 induces cell apoptosis by inhibition of STAT3 via up-regulation of SOCS3 expression in multiple myeloma
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DOI：
10.3324/haematol.2012.065607
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发表时间：
2013-02-01
期刊：
影响因子：
10.1
通讯作者：
Ng, Margaret H. L.
中科院分区：
文献类型：
--
作者：
Liang, Pei;Cheng, Suk Hang;Ng, Margaret H. L.
血小板因子4（PF 4）是一种抑制血管生成的趋化因子，可抑制肿瘤的生长和转移。我们先前发现多发性骨髓瘤中频繁的PF 4转录沉默，但这种趋化因子的功能作用仍然未知。我们研究了PF 4对骨髓瘤细胞株和原发性骨髓瘤细胞的凋亡作用，并探讨了其参与的信号通路。还使用小鼠模型研究了体内效应。PF 4不仅抑制骨髓瘤相关血管生成，而且抑制骨髓瘤细胞的生长并诱导其凋亡。我们发现，PF 4负性调节STAT 3，一致地抑制组成性和白细胞介素-6诱导的STAT 3磷酸化，并下调STAT 3靶基因（Mcl-1，Survivin和VEGF）的表达。组成性激活的STAT 3的过表达可以挽救PF 4诱导的凋亡效应。此外，我们发现PF 4诱导STAT 3抑制剂SOCS 3的表达，并且SOCS 3的基因沉默消除了其抑制STAT 3活化的能力，这表明SOCS 3在PF 4诱导的STAT 3抑制中起关键作用。LRP 1，一个假定的PF 4受体，敲低，也可以取消PF 4诱导的细胞凋亡和STAT 3抑制。最后，通过体内小鼠模型证实了PF 4的肿瘤生长抑制作用。从PF 4处理的小鼠的兔骨异种移植物的免疫染色显示诱导骨髓瘤细胞的凋亡和抑制血管生成，这与抑制STAT 3活性。总之，我们的临床前数据表明，PF 4可能是一种潜在的新的靶向药物，用于治疗骨髓瘤。
Platelet factor 4 (PF4) is an angiostatic chemokine that suppresses tumor growth and metastasis. We previously revealed frequent transcriptional silencing of PF4 in multiple myeloma, but the functional roles of this chemokine are still unknown. We studied the apoptotic effects of PF4 on myeloma cell lines and primary myeloma in vitro, and investigated the involved signaling pathway. The in vivo effects were also studied using a mouse model. PF4 not only suppressed myeloma-associated angiogenesis, but also inhibited growth and induced apoptosis in myeloma cells. We found that PF4 negatively regulated STAT3 and concordantly inhibited constitutive and interleukin-6-induced phosphorylation of STAT3, and down-regulated the expression of STAT3 target genes (Mcl-1, survivin and VEGF). Overexpression of constitutively activated STAT3 could rescue PF4-induced apoptotic effects. Furthermore, we found that PF4 induced the expression of SOCS3, a STAT3 inhibitor, and gene silencing of SOCS3 abolished its ability to inhibit STAT3 activation, suggesting a critical role of SOCS3 in PF4-induced STAT3 inhibition. Knockdown of LRP1, a putative PF4 receptor, could also abolish PF4-induced apoptosis and STAT3 inhibition. Finally, the tumor growth inhibitory effect of PF4 was confirmed by in vivo mouse models. Immunostaining of rabbit bone xenografts from PF4-treated mice showed induction of apoptosis of myeloma cells and inhibition of angiogenesis, which was associated with suppression of STAT3 activity. Together, our preclinical data indicate that PF4 may be a potential new targeting agent for the treatment of myeloma.