Soto-Cerrato Vanessa, Viñals Francesc, Lambert James R, Pérez-Tomás Ricardo
Department of Pathology and Experimental Therapeutics, Cancer Cell Biology Research Group, Universitat de Barcelona, and Laboratori de Recerca Translacional, ICO-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
Biochem Pharmacol. 2007 Nov 1;74(9):1340-9. doi: 10.1016/j.bcp.2007.07.016. Epub 2007 Jul 18.
The anticancer agent prodigiosin has been shown to act as an efficient immunosuppressant, eliciting cell cycle arrest at non-cytotoxic concentrations, and potent proapoptotic and antimetastatic effects at higher concentrations. Gene expression profiling of MCF-7 cells after treatment with a non-cytotoxic concentration of prodigiosin showed that expression of the p21WAF1/CIP1 gene, a negative cell cycle regulator was induced. In this study, we show that prodigiosin induces p21 expression leading to cell cycle blockade. Subsequently, we attempted to elucidate the molecular mechanisms involved in prodigiosin-mediated p21 gene expression. We demonstrate that prodigiosin induces p21 in a p53-independent manner as prodigiosin induced p21 in cells with both mutated and dominant negative p53. Conversely, the transforming growth factor-beta (TGF-beta) pathway has been found to be necessary for p21 induction. Prodigiosin-mediated p21 expression was blocked by SB431542, a TGF-beta receptor inhibitor. Nevertheless, this pathway alone is not enough to induce p21 expression. The TGF-beta family member (nonsteroidal anti-inflammatory drug)-activated gene 1/growth differentiation factor 15 (NAG-1) may activate this pathway, as it has previously been suggested to signal through the TGF-beta pathway and is overexpressed in response to prodigiosin treatment. We show that NAG-1 colocalizes with TGF-beta receptor type I, suggesting a possible interaction between them. Taken together, these results suggest the TGF-beta pathway is required for induction of p21 expression after prodigiosin treatment of MCF-7 cells.
抗癌药物灵菌红素已被证明可作为一种有效的免疫抑制剂，在非细胞毒性浓度下引起细胞周期停滞，并在较高浓度下具有强大的促凋亡和抗转移作用。用非细胞毒性浓度的灵菌红素处理MCF-7细胞后的基因表达谱显示，负性细胞周期调节因子p21WAF1/CIP1基因的表达被诱导。在本研究中，我们表明灵菌红素诱导p21表达导致细胞周期阻滞。随后，我们试图阐明灵菌红素介导的p21基因表达所涉及的分子机制。我们证明灵菌红素以p53非依赖的方式诱导p21，因为灵菌红素在具有突变型和显性阴性p53的细胞中均诱导p21表达。相反，已发现转化生长因子-β（TGF-β）途径对于p21的诱导是必需的。灵菌红素介导的p21表达被TGF-β受体抑制剂SB431542阻断。然而，仅该途径不足以诱导p21表达。TGF-β家族成员（非甾体抗炎药）激活基因1/生长分化因子15（NAG-1）可能激活该途径，因为先前有人提出它通过TGF-β途径发出信号，并且在对灵菌红素治疗的反应中过表达。我们表明NAG-1与I型TGF-β受体共定位，提示它们之间可能存在相互作用。综上所述，这些结果表明TGF-β途径是灵菌红素处理MCF-7细胞后诱导p21表达所必需的。
