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首页> 外文期刊>Cytokine >PEDF inhibits IL8 production in prostate cancer cells through PEDF receptor/phospholipase A2 and regulation of NFkappaB and PPARgamma.
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PEDF inhibits IL8 production in prostate cancer cells through PEDF receptor/phospholipase A2 and regulation of NFkappaB and PPARgamma.

机译：PEDF通过PEDF受体/磷脂酶A2以及NFkappaB和PPARgamma的调节来抑制前列腺癌细胞中IL8的产生。

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Interleukin-8 (IL8/CXCL8) has been described as a key effector in prostate cancer progression and resistance to standard chemotherapeutic drugs. In the present study, we investigated the effect of the natural, angio-inhibitory and anti-tumoral Pigment Epithelium-Derived Factor (PEDF) on the expression of IL8 cytokine by prostate cancer cells. Using a cytokine antibody array and ELISA, in addition to IL8 quantitative RT PCR, we showed that PEDF inhibits the production of IL8 in human hormone-refractory prostate cancer cells, and delays the growth of these cells in vitro. IL8 reduction was mimicked in cancer cells treated with PPARgamma agonist and NFkappaB-specific inhibitors. Accordingly, PPARgamma expression increased in response to PEDF, whereas RelA/p65 expression and nuclear localization, and NFkappaB transcriptional activity decreased. NFkappaB deactivation was reversed by the PPARgamma antagonist GW9662 and PPARgamma (Leu(468)/Glu(471)) dominant negative suggesting a PPARgamma-dependent process. We also investigated PEDF Receptor/PLA2 as key player in this pathway by small interference RNA. PEDFR knock down in prostate cancer cells reversed PEDF-induced PPARgamma up-regulation, and NFkappaB and IL8 inhibition compared to non-targeting control siRNA. We conclude that by binding to PEDFR, PEDF up-regulates PPARgamma, leading subsequently to suppressed NFkappaB-mediated transcriptional activation, reduced production of IL8 and limited proliferation of prostate cancer cells. These results reinforce PEDF's therapeutic potential and imply that blocking IL8 could represent a novel alternative for prostate cancer treatment.
机译：白介素8（IL8 / CXCL8）被描述为前列腺癌进展和对标准化疗药物耐药的关键效应物。在本研究中，我们研究了天然，血管抑制和抗肿瘤色素上皮衍生因子（PEDF）对前列腺癌细胞表达IL8细胞因子的影响。使用细胞因子抗体阵列和ELISA，除了IL8定量RT PCR外，我们还显示PEDF抑制人激素难治性前列腺癌细胞中IL8的产生，并延迟了这些细胞的体外生长。在用PPARγ激动剂和NFkappaB特异性抑制剂治疗的癌细胞中模仿了IL8的降低。因此，响应于PEDF，PPARgamma表达增加，而RelA / p65表达和核定位以及NFkappB转录活性降低。 NFkappaB失活被PPARgamma拮抗剂GW9662和PPARgamma（Leu（468）/ Glu（471））显性阴性逆转，提示PPARgamma依赖性过程。我们还通过小干扰RNA研究了PEDF受体/ PLA2在该途径中的关键作用。与非靶向对照siRNA相比，前列腺癌细胞中的PEDFR降低可逆转PEDF诱导的PPARgamma上调，并且NFkappaB和IL8抑制作用。我们得出结论，通过与PEDFR结合，PEDF上调PPARgamma，从而导致抑制NFkappaB介导的转录激活，降低IL8的产生和限制前列腺癌细胞的增殖。这些结果增强了PEDF的治疗潜力，并暗示阻断IL8可能代表前列腺癌治疗的新选择。

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