Resveratrol enhances prostate cancer cell response to ionizing radiation. Modulation of the AMPK, Akt and mTOR pathways.
Resveratrol enhances prostate cancer cell response to ionizing radiation. Modulation of the AMPK, Akt and mTOR pathways.
复制标题
DOI：
10.1186/1748-717x-6-144
复制
发表时间：
2011-10-26
期刊：
影响因子：
--
通讯作者：
Tsakiridis T
中科院分区：
文献类型：
--
作者：
Rashid A;Liu C;Sanli T;Tsiani E;Singh G;Bristow RG;Dayes I;Lukka H;Wright J;Tsakiridis T
前列腺癌（PrCa）显示出对放射治疗（RT）的抗性，需要放射治疗剂量递增，这与更大的毒性相关。这突出了开发辐射增敏剂以提高RT在PrCa中的功效的需要。电离辐射（IR）刺激由蛋白激酶Akt介导的IR抗性和存活途径，但它也激活代谢能量传感器和肿瘤抑制因子AMP活化蛋白激酶（AMPK）。在这里，我们研究了多酚白藜芦醇（RSV）对IR诱导的细胞存活抑制，细胞周期调节和PrCa细胞分子反应的影响。用单独的RSV（2.5-10 μM）或与IR（2-8戈伊）组合处理雄激素不敏感（PC 3）、敏感（22 RV 1）PrCa和PNT 1A正常前列腺上皮细胞。进行克隆形成试验、细胞周期分析、显微镜检查和免疫印迹以评估存活率、细胞周期进展和分子应答。RSV（2.5-5 μM）抑制PC 3和22 RV 1细胞的克隆形成存活，但不抑制正常前列腺PNT 1A细胞。RSV特异性地使PrCa细胞对IR敏感，诱导细胞周期停滞在G1-S期，并增强IR诱导的核畸变和凋亡。RSV增强了IR诱导的DNA损伤（γ H2 Ax）和凋亡（裂解型半胱天冬酶3）标记物以及细胞周期调节因子p53、p21 cip 1和p27 kip 1的表达。RSV增强ATM和AMPK的IR激活，但抑制Akt的基础和IR诱导的磷酸化。我们的研究结果表明，RSV可能通过激活ATM-AMPK-p53-p21 cip 1/p27 kip 1和抑制Akt信号通路的双重作用，阻滞细胞周期，促进细胞凋亡，并使PrCa细胞对IR敏感。
Prostate cancer (PrCa) displays resistance to radiotherapy (RT) and requires radiotherapy dose escalation which is associated with greater toxicity. This highlights a need to develop radiation sensitizers to improve the efficacy of RT in PrCa. Ionizing radiation (IR) stimulates pathways of IR-resistance and survival mediated by the protein kinase Akt but it also activates the metabolic energy sensor and tumor suppressor AMP-Activated Protein Kinase (AMPK). Here, we examined the effects of the polyphenol resveratrol (RSV) on the IR-induced inhibition of cell survival, modulation of cell cycle and molecular responses in PrCa cells. Androgen-insensitive (PC3), sensitive (22RV1) PrCa and PNT1A normal prostate epithelial cells were treated with RSV alone (2.5-10 μM) or in combination with IR (2-8 Gy). Clonogenic assays, cell cycle analysis, microscopy and immunoblotting were performed to assess survival, cell cycle progression and molecular responses. RSV (2.5-5 μM) inhibited clonogenic survival of PC3 and 22RV1 cells but not of normal prostate PNT1A cells. RSV specifically sensitized PrCa cells to IR, induced cell cycle arrest at G1-S phase and enhanced IR-induced nuclear aberrations and apoptosis. RSV enhanced IR-induced expression of DNA damage (γH2Ax) and apoptosis (cleaved-caspase 3) markers as well as of the cell cycle regulators p53, p21cip1 and p27kip1. RSV enhanced IR-activation of ATM and AMPK but inhibited basal and IR-induced phosphorylation of Akt. Our results suggest that RSV arrests cell cycle, promotes apoptosis and sensitizes PrCa cells to IR likely through a desirable dual action to activate the ATM-AMPK-p53-p21cip1/p27kip1 and inhibit the Akt signalling pathways.