Dal Col Jessica, Zancai Paola, Terrin Liliana, Guidoboni Massimo, Ponzoni Maurilio, Pavan Alessandro, Spina Michele, Bergamin Stefano, Rizzo Silvana, Tirelli Umberto, De Rossi Anita, Doglioni Claudio, Dolcetti Riccardo
Cancer Bio-Immunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico (CRO), Istituto di Ricovero e Cura a Caratiere Scientifico (IRCCS) National Cancer Institute, Aviano, Italy.
Blood. 2008 May 15;111(10):5142-51. doi: 10.1182/blood-2007-07-103481. Epub 2008 Mar 13.
Functional characterization of signaling pathways that critically control mantle cell lymphoma (MCL) cell growth and survival is relevant to designing new therapies for this lymphoma. We herein demonstrate that the constitutive activation of Akt correlates with the expression of the phosphorylated, inactive form of PTEN. Phosphatidyl-inositol-3 kinase (PI3-K)/Akt or mammalian target of rapamycin (mTOR) inhibition decreased the growth of both primary MCL cultures and established cell lines and antagonizes the growth-promoting activity of CD40 triggering and IL-4. These effects are mediated by nuclear accumulation of the p27(Kip1) inhibitor induced by down-regulation of the p45(Skp2) and Cks1 proteins, which target p27(Kip1) for degradation. Moreover, Akt inhibition down-regulated cyclin D1 by promoting its proteasome-dependent degradation driven by GSK-3. Intriguingly, mTOR inhibition affected cyclin D1 proteolysis only in MCL cells in which GSK-3 is under the direct control of mTOR, suggesting that different MCL subsets could be differently responsive to mTOR inhibition. Finally, PI3-K/Akt inhibitors, but not rapamycin, induced variable levels of caspase-dependent apoptosis and reduced telomerase activity. These results indicate that Akt and mTOR activation have distinct functional relevance in MCL and suggest that targeting Akt may result in more effective therapeutic effects compared with mTOR inhibition.
对严重控制套细胞淋巴瘤（MCL）细胞生长和存活的信号通路进行功能表征，对于设计针对这种淋巴瘤的新疗法具有重要意义。我们在此证明，Akt的组成性激活与磷酸化的、无活性形式的PTEN的表达相关。磷脂酰肌醇-3激酶（PI3-K）/Akt或雷帕霉素哺乳动物靶点（mTOR）的抑制降低了原发性MCL培养物和已建立细胞系的生长，并拮抗CD40触发和IL-4的促生长活性。这些效应是由p45（Skp2）和Cks1蛋白下调诱导的p27（Kip1）抑制剂的核积累介导的，p45（Skp2）和Cks1蛋白靶向p27（Kip1）进行降解。此外，Akt抑制通过促进由GSK-3驱动的其蛋白酶体依赖性降解来下调细胞周期蛋白D1。有趣的是，mTOR抑制仅在GSK-3受mTOR直接控制的MCL细胞中影响细胞周期蛋白D1的蛋白水解，这表明不同的MCL亚群对mTOR抑制可能有不同的反应。最后，PI3-K/Akt抑制剂而非雷帕霉素诱导了不同水平的半胱天冬酶依赖性凋亡并降低了端粒酶活性。这些结果表明，Akt和mTOR激活在MCL中具有不同的功能相关性，并表明与mTOR抑制相比，靶向Akt可能产生更有效的治疗效果。
