苏州大学王志伟谈SKP2研究进展

越来越多的证据表明，Skp2在肿瘤发生发展中起着癌基因的作用。很显然，Skp2通过降解其底物发挥生理功能，包括p21，p27，p57，p53，Foxo1。据报道，Skp2的过表达与乳腺癌的预后不良相关。此外，Skp2过表达能促进乳腺癌细胞增殖，而抑制Skp2表达则能抑制细胞增殖。我们的观察结果与此类似，表明Skp2能促进乳腺癌细胞生长。Hung等人报道了Skp2在肺癌细胞中过表达能促进细胞侵袭，目前研究中，我们发现Skp2过表达能促进乳腺癌细胞的侵袭和迁移，而下调Skp2能阻滞细胞迁移。所以研究结果表明，Skp2是乳腺癌细胞中的癌基因，靶向Skp2将会是治疗乳腺癌细胞的有效办法。

由于Skp2在肿瘤发展过程中是癌基因作用，Skp2的失活有可能有助于人类癌症治疗。为此，多个课题组在探索Skp2抑制剂。例如，Compound A被发现能阻断Skp2 E3泛素连接酶活性。另一种Skp2抑制剂称为Compound 25，据报道能够抑制Akt介导的糖酵解和诱导细胞衰老。然而，这些化学抑制剂都有副作用，所以最重要的是找到没有毒副作用的天然化合物用来使人类肿瘤细胞中的Skp2失活。事实上，已经报道了几种天然化合物，包括curcumin姜黄素，butylidenephthalide丁苯酞，Flavokawain A（FKA）和Salinomycin。在本研究中，我们探索了天然化合物Rottlerin是否可能是乳腺癌中Skp2的潜在抑制剂。我们证实，Rottlerin在乳腺癌细胞中能抑制Skp2的表达。更重要的是，我们确定Rottlerin通过抑制Skp2发挥其抗肿瘤功能。总之，为了确定Rottlerin的功能作用，以后还需要更多地实验研究，动物模型实验和临床实验。

最近，多项研究已经证明，Rottlerin在乳腺癌细胞中表现出抗肿瘤活性。例如Rottlerin诱导LRP6降解，抑制乳腺癌细胞中mTORC1和Wnt /β-catenin信号传导。在其他人类恶性肿瘤中，也有很多Rottlerin的相关研究。Basu等人报道了Rottlerin通过泛素蛋白酶体介导的途径下调caspase-2的活化，导致HeLa细胞和卵巢癌细胞的细胞凋亡。Lim等人观察到，通过在人结肠癌细胞和其他肿瘤细胞中CHOP（CCAAT /增强子结合蛋白同源蛋白）和NAG-1（非甾体抗炎药物活化的基因-1）的上调，Rottlerin能诱导内质网应激性凋亡。Park等人发现Rottlerin通过调控结肠癌细胞中的ROS（活性氧）使HO-1（血红素加氧酶-1）上调。值得注意的是，Rottlerin通过增强前列腺癌细胞中TOP1cc（拓扑异构酶I切割复合物）的形成和稳定性而增强喜树碱介导的细胞毒性。此外，一项研究确定，Rottlerin通过与胰腺癌细胞中Bcl-2家族蛋白的相互作用刺激细胞凋亡[43]。值得注意的是，Huang等人揭示了Rottlerin通过靶向调控多种信号通路，包括Akt，Notch和Shh（sonic hedgehog）途径抑制胰腺癌细胞生长。有趣的是，除了凋亡，Rottlerin在几种癌细胞系中被发现有诱导细胞自噬的能力。人类纤维肉瘤细胞中，Rottlerin通过PKCd独自作用的方式介导细胞自噬。同样的，在前列腺癌、乳腺癌、胰腺癌中，Rottlerin通过抑制细胞中的PI3K / Akt / mTOR途径诱发细胞自噬。在滤泡性甲状腺癌细胞中，Rottlerin通过使粘附复合体不稳定，从而阻滞细胞迁移。此外，据报道，Rottlerin通过阻止NF-κB核迁移和DNA结合活性，并随后下调NF-κB靶基因，最终抑制血管生成。根据这些实验发现，我们发现Rottlerin能抑制细胞生长，诱导细胞凋亡，阻滞细胞周期，阻止乳腺癌细胞的迁移和侵袭。

苏州大学王志伟发表的相关文章

Oncotarget. 2016 Oct 11;7(41):66512-66524. doi: 10.18632/oncotarget.11614.

Rottlerin exerts its anti-tumor activity through inhibition of Skp2 in breast cancer cells.

Yin X1, Zhang Y2, Su J1, Hou Y1, Wang L1, Ye X1, Zhao Z1, Zhou X1, Li Y3, Wang Z1,4.

Abstract

Studies have investigated the tumor suppressive role of rottlerin in carcinogenesis. However, the molecular mechanisms of rottlerin-induced anti-tumor activity are largely unclear. Skp2 (S-phase kinase associated protein 2) has been validated to play an oncogenic role in a variety of human malignancies. Therefore, inactivation of Skp2 could be helpful for the treatment of human cancers. In the current study, we explore whether rottlerin could inhibit Skp2 expression, leading to inhibition of cell growth, migration and invasion in breast cancer cells. We found that rottlerin treatment inhibited cell growth, induced apoptosis and cell cycle arrest. We also revealed that rottlerin suppressed cell migration and invasion in breast cancer cells. Mechanically, we observed that rottlerin significantly down-regulated the expression of Skp2 in breast cancer cells. Importantly, overexpression of Skp2 abrogated rottlerin-mediated tumor suppressive activity, whereas down-regulation of Skp2enhanced rottlerin-triggered anti-tumor function. Strikingly, we identified that rottlerin exhibited its anti-tumor potential partly through inactivation of Skp2 in breast cancer. Our findings indicate that rottlerin could be a potential safe agent for the treatment of breast cancer.

Oncotarget. 2012 Nov;3(11):1294-300.

Identification of acetylation-dependent regulatory mechanisms that govern the oncogenic functions of Skp2.

Abstract

The Skp2 (S-phase kinase associated protein 2) oncoprotein is often highly expressed in various types of human cancers. However, the mechanistic basis of its oncogenic function, as well as the upstream regulatory pathway(s) that control Skp2 activities remains not fully understood. Recently, we reported that p300 acetylates Skp2 at two conserved lysine residues K68 and K71 within its NLS (Nuclear localization signal). This modification leads to increased Skp2 stability and cytoplasmic translocation, thus contributing to elevated Skp2oncogenic potential. Moreover, we found that the SIRT3 tumor suppressor serves as the physiological deacetylase that antagonizes p300-mediated Skp2 acetylation. Furthermore, we showed that Skp2 governs E-cadherin ubiquitination and degradation in the cytosol. Consistent with this, we observed an inverse correlation between Skp2 and E-cadherin expression in clinical breast tumor samples. Therefore, our work elucidates a novel acetylation-dependent regulatory mechanism for Skp2 oncogenic functions.

Biochim Biophys Acta. 2012 Jan;1825(1):11-7. doi: 10.1016/j.bbcan.2011.09.002. Epub 2011 Sep 22.

Skp2: a novel potential therapeutic target for prostate cancer.

Abstract

Prostate cancer is the most frequently diagnosed tumor in men and the second most common cause of cancer-related death for males in the United States. It has been shown that multiple signaling pathways are involved in the pathogenesis of prostate cancer, such as androgen receptor (AR), Akt, Wnt, Hedgehog (Hh) and Notch. Recently, burgeoning amounts of evidence have implicated that the F-box protein Skp2(S-phase kinase associated protein 2), a well-characterized oncoprotein, also plays a critical role in the development and progression of prostate cancer. Therefore, this review discusses the recent literature regarding the function and regulation of Skp2 in the pathogenesis of prostate cancer. Furthermore, we highlight that Skp2 may represent an attractive therapeutic target, thus warrants further development of agents to target Skp2, which could have significant therapeutic impact on prostate cancer.