Diosmetin Induces Modulation of Igf-1 and Il-6 Levels to Alter Rictor-Akt-PKCα Cascade in Inhibition of Prostate Cancer.
Diosmetin Induces Modulation of Igf-1 and Il-6 Levels to Alter Rictor-Akt-PKCα Cascade in Inhibition of Prostate Cancer.
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DOI：
10.3390/jcm10204741
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发表时间：
2021-10-15
影响因子：
3.9
通讯作者：
Shukla S
中科院分区：
文献类型：
--
作者：
Pakradooni R;Shukla N;Gupta K;Kumar J;Isali I;Khalifa AO;Shukla S
生长信号通常来源于周围的微环境，对细胞很重要。然而，当生长因子的刺激变得过度并超过其阈值时，可能会产生有害影响。在癌症患者中，肿瘤的维持至少部分取决于生长因子的刺激，这也可以促进癌症进展到晚期。当肿瘤生长超出其组织边界或当它侵入并定植于其他组织时，这一点尤其重要。已知这些上述恶性事件部分由升高的细胞因子水平支持。在目前已知的生长信号中，胰岛素样生长因子（IGF）-1和IL-6先前已被研究其在前列腺癌中的作用。IGF-1和IL-6均激活MTOR复合物2（Rictor）/AKT/蛋白激酶C α（PKCα）信号通路的RAPTOR非依赖性伴侣，是其下游作用机制之一。目前，研究工作主要集中在探索改变生长因子（如IGF-1）和细胞因子（如IL-6）信号传导的试剂，以用于其作为治疗剂的潜在应用，因为已报道这两者都调节疾病结果。在本研究中，IGF-1和IL-6在雄激素响应性LNCaP细胞系和雄激素难治性PC-3细胞系中以剂量和时间依赖性方式发挥不同的作用。IGF-1和IL-6处理后，Thr-1135残基的Rictor、Ser-473残基的AKT和Ser-657残基的PKCα磷酸化水平均升高。随后，人们发现天然植物苷元薯蓣皂苷具有调节Rictor/AKT/PKCα下游信号级联的潜力，从而抑制前列腺癌的进展。Diosmetin处理LNCaP和PC-3细胞后，Rictor（Thr-1135）、AKT（Ser-473）和PKCα（Ser-657）的磷酸化水平呈剂量依赖性降低。此外，Bax/Bcl-2的表达比例增加，响应于薯蓣皂苷处理，这将导致细胞凋亡增加。基于这些观察，薯蓣皂苷可能代表前列腺癌的新的治疗靶点。
Growth signals, which typically originate from the surrounding microenvironment, are important for cells. However, when stimulation by growth factors becomes excessive and exceeds their threshold limit, deleterious effects may ensue. In patients with cancer, maintenance of tumors depends, at least in part, on growth factor stimulation, which can also facilitate cancer progression into advanced stages. This is particularly important when the tumor grows beyond its tissue boundaries or when it invades and colonizes other tissues. These aforementioned malignant events are known to be partly supported by elevated cytokine levels. Among the currently known growth signals, insulin-like growth factor (IGF)-1 and IL-6 have been previously studied for their roles in prostate cancer. Both IGF-1 and IL-6 have been reported to activate the RAPTOR independent companion of MTOR complex 2 (Rictor)/AKT/protein kinase C α (PKCα) signaling pathway as one of their downstream mechanisms. At present, research efforts are mainly focused on the exploration of agents that alter growth factor (such as IGF-1) and cytokine (such as IL-6) signaling for their potential application as therapeutic agents, as both of these have been reported to modulate disease outcome. In the present study, IGF-1 and IL-6 served distinct roles in the androgen responsive LNCaP cell line and in the androgen refractory PC-3 cell line in a dose- and time-dependent manner. Increased phosphorylation of Rictor at the Thr-1135 residue, AKT at the Ser-473 residue and PKCα at the Ser-657 residue were observed after treatment with IGF-1 and IL-6. Subsequently, it was found that diosmetin, a natural plant aglycone, had the potential to modulate the downstream signaling cascade of Rictor/AKT/PKCα to inhibit the progression of prostate cancer. Treatment of LNCaP and PC-3 cells with diosmetin inhibited the phosphorylation of Rictor (Thr-1135), AKT (Ser-473) and PKCα (Ser-657) in a dose-dependent manner. Furthermore, the Bax/Bcl-2 expression ratio was increased in response to diosmetin treatment, which would result in increased apoptosis. Based on these observations, diosmetin may represent a novel therapeutic target for prostate cancer.
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