Matrix protein CCN1 is critical for prostate carcinoma cell proliferation and TRAIL-induced apoptosis.
Matrix protein CCN1 is critical for prostate carcinoma cell proliferation and TRAIL-induced apoptosis.
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DOI：
10.1158/1541-7786.mcr-09-0017
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发表时间：
2009-07
期刊：
影响因子：
--
通讯作者：
Lau LF
中科院分区：
文献类型：
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作者：
Franzen CA;Chen CC;Todorović V;Juric V;Monzon RI;Lau LF
肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis inducing ligand，TRAIL）在免疫监视中起重要作用，能优先诱导肿瘤细胞凋亡，在肿瘤治疗中具有潜在的应用价值。然而，其选择性杀死癌细胞的分子基础还不清楚。最近的研究已经鉴定了整合素结合基质细胞蛋白的CCN家族作为细胞行为的重要调节剂，包括细胞粘附、增殖、迁移、分化和存活。我们在这里表明，CCN 1（CYR 61）通过整合素和硫酸乙酰肝素蛋白聚糖（HSPGs）支持前列腺癌细胞作为粘附底物的粘附。在PC-3和DU-145雄激素非依赖性前列腺癌细胞中敲低CCN 1表达强烈抑制其增殖而不引起凋亡，表明CCN 1促进其生长。然而，CCN 1还通过与整合素αvβ3、α6β4和细胞表面HSPG多配体蛋白聚糖-4相互作用显著增强TRAIL诱导的细胞凋亡，通过PKCα依赖性机制起作用，而不需要从头蛋白合成。在PC-3、DU-145和LNCaP细胞中敲低CCN 1表达严重减弱了它们对TRAIL的敏感性，这种作用可被外源性添加的CCN 1蛋白逆转。这些发现揭示了前列腺癌细胞中CCN 1的功能二分法，因为它有助于细胞增殖和TRAIL诱导的细胞死亡，并表明CCN 1表达状态可能是评估TRAIL依赖性癌症治疗疗效的重要参数。
Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) plays an important role in immune surveillance and preferentially induces apoptosis in cancer cells over normal cells, suggesting its potential in cancer therapy. However, the molecular basis for its selective killing of cancer cells is not well understood. Recent studies have identified the CCN family of integrin-binding matricellular proteins as important regulators of cell behavior, including cell adhesion, proliferation, migration, differentiation, and survival. We show here that CCN1 (CYR61) supports the adhesion of prostatic carcinoma cells as an adhesion substrate through integrins and heparan sulfate proteoglycans (HSPGs). Knockdown of CCN1 expression in PC-3 and DU-145 androgen-independent prostate cancer cells strongly inhibited their proliferation without causing apoptosis, indicating that CCN1 promotes their growth. However, CCN1 also significantly enhances TRAIL-induced apoptosis through interaction with integrins αvβ3, α6β4, and the cell surface HSPG syndecan-4, acting through a PKCα-dependent mechanism without requiring de novo protein synthesis. Knockdown of CCN1 expression in PC-3, DU-145, and LNCaP cells severely blunted their sensitivity to TRAIL, an effect that was reversed by exogenously added CCN1 protein. These findings reveal a functional dichotomy for CCN1 in prostate carcinoma cells since it contributes to both cell proliferation and TRAIL-induced cell death, and suggest that CCN1 expression status may be an important parameter in assessing the efficacy of TRAIL-dependent cancer therapy.