Resveratrol Inhibits Non-small Cell Lung Cancer via Directly Targeting EGFR and c-Met Signaling Pathways
-
摘要:目的
探讨白藜芦醇抑制非小细胞肺癌细胞增殖的分子机制。
方法非小细胞肺癌细胞用白藜芦醇处理24、48和72 h，MTS和软琼脂集落形成实验检测白藜芦醇对非小细胞肺癌的抑制作用，免疫印迹检测白藜芦醇对表皮生长因子受体（epidermal growth factor receptor, EGFR）和肝细胞生长因子受体（c-Met）表达水平及下游信号通路的影响，流式细胞术检测白藜芦醇对细胞周期的影响。
结果白藜芦醇剂量依赖性抑制非小细胞肺癌细胞的增殖。白藜芦醇抑制EGFR和c-Met信号通路磷酸化活化的同时下调了EGFR总蛋白及EGFR在胞膜和胞核的表达，同时降低了c-Met蛋白在胞膜的表达及c-Met蛋白60 kD大小剪切体在胞核的表达。白藜芦醇促进了A549细胞G0/G1期阻滞。
结论白藜芦醇通过靶向EGFR和c-Met信号通路抑制非小细胞肺癌细胞的增殖。
Abstract:ObjectiveTo investigate the mechanism of resveratrol-mediated inhibition effect on human non-small cell lung cancer.
MethodsNon-small cell lung cancer cells were treated with various concentrations of resveratrol for 24, 48 and 72 h, the proliferation was evaluated by MTS and soft agar assay. Meanwhile, the activation of EGFR and c-Met signaling pathways after resveratrol treatment was tested via immunoblotting. The subcellular localization of EGFR and c-Met were assessed by Western blot. Flow cytometry was conducted to detect cell cycle progression.
ResultsResveratrol inhibited the proliferation of non-small cell lung cancer cells in a dose-dependent manner. Moreover, resveratrol treatment not only suppressed the phosphorylation of EGFR and c-Met signaling pathways, but also resulted in the down-regulation of total EGFR protein expression level, as well as its localization on membrane and in nucleus. Additionally, resveratrol treatment decreased c-Met expression on membrane and inhibited the 60 kD cleaved variant of c-Met translocated into nucleus. Flow cytometry data demonstrated that resveratrol induced cell cycle G0/G1 arrest.
ConclusionResveratrol inhibits human non-small cell lung cancer via directly targeting EGFR and c-Met signaling pathways.
-
Key words:
- Non-small cell lung caner /
- Resveratrol /
- EGFR /
- c-Met
-
-
![]()
图 1 白藜芦醇抑制A549和HCC827细胞的停泊依赖性增殖
Figure 1 Resveratrol inhibited anchorage-dependent growth of A549 and HCC827 cells
![]()
图 2 白藜芦醇抑制A549和HCC827细胞停泊非依赖生长
Figure 2 Resveratrol inhibited anchorage-independent growth of A549 and HCC827 cells
![]()
图 3 白藜芦醇抑制A549细胞c-Met和EGFR信号通路的活化
Figure 3 Resveratrol suppressed activation of c-Met and EGFR signaling pathways in A549 cells
![]()
图 4 白藜芦醇下调A549细胞内EGFR和c-Met的蛋白表达
Figure 4 Resveratrol down-regulated expression of EGFR and c-Met in A549 cells
![]()
图 5 白藜芦醇促进EGFR和c-Met蛋白泛素化降解
Figure 5 Resveratrol promotes ubiquitination-mediated degradation of EGFR and c-Met
-
[1] Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012[J]. CA Cancer J Clin, 2012, 62(1): 10-29. doi: 10.3322/caac.20138
[2] Herbst RS, Heymach JV, Lippman SM. Lung cancer[J]. N Engl J Med, 2008, 359 (13): 1367-80. doi: 10.1056/NEJMra0802714
[3] Ramalingam SS, Owonikoko TK, Khuri FR. Lung cancer: New biological insights and recent therapeutic advances[J]. CA Cancer J Clin, 2011, 61(2): 91-112. doi: 10.3322/caac.v61:2
[4] Klein EA, Assoian RK. Transcriptional regulation of the cyclin D1 gene at a glance[J]. J Cell Sci, 2008, 121 (Pt23): 3853-7. https://www.researchgate.net/publication/23484375_Transcriptional_regulation_of_the_cyclin_D1_gene_at_a_glance
[5] Bode AM, Dong Z. Cancer prevention research-then and now[J]. Nat Rev Cancer, 2009, 9(7): 508-16. doi: 10.1038/nrc2646
[6] Novelle MG, Wahl D, Diéguez C, et al. Resveratrol supplementation: Where are we now and where should we go?[J]. Ageing Res Rev, 2015, 21: 1-15. doi: 10.1016/j.arr.2015.01.002
[7] Gescher A, Steward WP, Brown K. Resveratrol in the management of human cancer: how strong is the clinical evidence?[J]. Ann N Y Acad Sci, 2013, 1290: 12-20. doi: 10.1111/nyas.12205
[8] Park EJ, Pezzuto JM. The pharmacology of resveratrol in animals and humans[J]. Biochim Biophys Acta, 2015, 1852(6): 1071-113. doi: 10.1016/j.bbadis.2015.01.014
[9] Tebbutt N, Pedersen MW, Johns TG. Targeting the ERBB family in cancer: couples therapy[J]. Nat Rev Cancer, 2013, 13(9): 663-73. doi: 10.1038/nrc3559
[10] Herbst RS, Fukuoka M, Baselga J. Gefitinib-a novel targeted approach to treating cancer[J]. Nat Rev Cancer, 2004, 4(12): 956-65. doi: 10.1038/nrc1506
[11] Wheeler DL, Dunn EF, Harari PM. Understanding resistance to EGFR inhibitors-impact on future treatment strategies[J]. Nat Rev Clinl Oncol, 2010, 7(9): 493-507. doi: 10.1038/nrclinonc.2010.97
[12] Tan CS, Gilligan D, Pacey S. Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer[J]. Lancet Oncol, 2015, 16(9): e447-59. doi: 10.1016/S1470-2045(15)00246-6
[13] Juchum M, Günther M, Laufer SA. Fighting cancer drug resistance: Opportunities and challenges for mutation-specific EGFR inhibitors[J]. Drug Resist Update, 2015, 20: 12-28, . doi: 10.1016/j.drup.2015.05.002
[14] Lo HW. Nuclear mode of the EGFR signaling network: biology, prognostic value, and therapeutic implications[J]. Disco Med, 2010, 10(50): 44-51. https://www.researchgate.net/publication/45423332_Nuclear_Mode_of_the_EGFR_Signaling_Network_Biology_Prognostic_Value_and_Therapeutic_Implications
[15] Spohn L, Fichter C, Werner M, et al. Subcellular localization of EGFR in esophageal carcinoma cell lines[J]. J Cell Commun Signal, 2016, 10(1): 41-7. doi: 10.1007/s12079-015-0308-4
[16] Dittmann K, Mayer C, Paasch A, et al. Nuclear EGFR renders cells radio-resistant by binding mRNA species and triggering a metabolic switch to increase lactate production[J]. Radiother Oncol, 2015, 116(3): 431-7. doi: 10.1016/j.radonc.2015.08.016
[17] Pozner-Moulis S, Pappas DJ, Rimm DL. Met, the hepatocyte growth factor receptor, localizes to the nucleus in cells at low density[J]. Cancer Res, 2006, 66(16): 7976-82. doi: 10.1158/0008-5472.CAN-05-4335
[18] Matteucci E, Bendinelli P, Desiderio MA. Nuclear localization of active HGF receptor Met in aggressive MDA-MB231 breast carcinoma cells[J]. Carcinogenesis, 2009, 30(6): 937-45. doi: 10.1093/carcin/bgp080
[19] Chaudhary SC, Cho MG, Nguyen TT, et al. A putative pH-dependent nuclear localization signal in the juxtamembrane region of c-Met[J]. Exp Mol Med, 2014, 46: e119. doi: 10.1038/emm.2014.67
下载:
计量
- 文章访问数: 1721
- HTML全文浏览量: 350
- PDF下载量: 1109
