|
|
- 2016
异丙酚通过激活PI3K/Akt信号通路抑制癌细胞转移
|
Abstract:
摘要：目的 研究异丙酚对肿瘤细胞转移相关信号通路PI3K/Akt的影响。方法 将来源于人类乳腺癌细胞株移植到SPF级裸基因的免疫缺陷型小鼠制备乳腺癌模型。将接种成功小鼠随机分为4组：对照组(C组，n=6)、异丙酚输注组(P组，50mg/kg，输注2h，n=6)、PI3K抑制剂(BYL719)组(B组，n=6)和异丙酚加PI3K抑制剂组(P+B组，n=6)。于给药后4周分别采用蛋白质免疫印迹试验(Western blot)检测4组小鼠癌组织中PI3K、磷酸化Akt(p-Akt)、Akt的蛋白表达水平，逆转录-聚合酶链反应(RT-PCR)检测PI3KR1(PI3K regulatory subunit 1)和Akt(Akt1和Akt2)的mRNA表达水平；取双肺，观察小鼠肺表面转移结节数。结果 与C组相比，P组PI3K和p-Akt的蛋白表达明显增高(P<0.05)，PI3KR1的mRNA表达明显升高(P<0.05)，Akt1和Akt2的mRNA表达无明显变化(P>0.05)，肺表面转移结节数明显减少(P<0.05)；B组PI3K和p-Akt的蛋白表达明显下调(P<0.05)，PI3KR1 mRNA、Akt1和Akt2的mRNA表达无明显变化(P>0.05)，肺表面结节数明显增加(P<0.05)。与B组相比，P+B组明显上调了 PI3K和p-Akt的蛋白表达(P<0.05)，PI3KR1的mRNA表达明显升高(P<0.05)，Akt1和Akt2的mRNA表达无明显变化(P>0.05)，肺表面结节数明显减少(P<0.05)。结论 异丙酚可通过激活PI3K/Akt信号通路抑制肿瘤细胞的转移。
ABSTRACT: Objective To study the effects of propofol on the metastasis of tumor cells related PI3K/Akt signaling pathway. Methods The breast cancer model was established by transplanting human derived breast cancer cell lines into immunodeficient mice with naked gene. The mice, inoculated successfully, were randomly divided into 4 groups: control group (C group, n=6), propofol group (P group, n=6), propofol+PI3K inhibitor (BYL719) group (P+B group, n=6), and PI3K inhibitor group (BYL719) (B group, n=6). The expressions of PI3K, p-Akt and Akt were examined by Western blot at week 4 after administration; the gene levels of PI3KR1, Akt1 and Akt2 were detected by RT-PCR at week 4 after administration; the number of metastatic lung nodules from both lungs was also observed at week 4 after administration. Results Compared with those in C group, the expressions of PI3K and p-Akt were significantly higher in P group (P<0.05), the level of PI3KR1 mRNA but not Akt1 and Akt2 mRNA was significantly increased(P<0.05), and metastatic lung nodules significantly decreased (P<0.05). In B group, the expressions of PI3K and p-Akt were significantly decreased (P<0.05), the levels of PI3KR1, Akt1 and Akt2 mRNA were not significantly increased (P>0.05), but metastatic lung nodules significantly increased (P<0.05). Compared with those in B group, in P+B group the expressions of PI3K and p-Akt were markedly higher (P<0.05), the level of PI3KR1 mRNA but not Akt1 and Akt2 mRNA was significantly increased (P<0.05), and metastatic lung nodules significantly decreased (P<0.05). Conclusion Propofol can inhibit the metastasis of tumor cells through the upregulated and activated PI3K/Akt signaling pathway
| [1] | AN G, KULKARNI S. An agent-based modeling framework linking inflammation and cancer using evolutionary principles: Description of a generative hierarchy for the hallmarks of cancer and developing a bridge between mechanism and epidemiological data[J]. Math Biosci, 2015, 260(1):16-24. |
| [2] | BASELGA J. Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer[J]. Oncologist, 2011, 16(Suppl 1):12-19. |
| [3] | GOKCINAR D, ERGIN V, CUMAOGLU A, et al. Effects of ketamine, propofol, and ketofol on proinflammatory cytokines and markers of oxidative stress in a rat model of endotoxemia-induced acute lung injury[J]. Acta Biochim Pol, 2013, 60(3):451-456. |
| [4] | GAROFALO A, CHIRIVI RG, SCANZIANI E, et al. Comparative study on the metastatic behavior of human tumors in nude, beige/nude/xid and severe combined immunodeficient mice[J]. Invasion Metastasis, 1993, 13(2):82-91. |
| [5] | WU Y, ZHOU BP. Inflammation: a driving force speeds cancer metastasis[J]. Cell Cycle, 2009, 8(20):3267-3273. |
| [6] | HSING CH, LIN MC, CHOI PC, et al. Anesthetic propofol reduces endotoxic inflammation by inhibiting reactive oxygen species-regulated Akt/IKKβ/NF-κB signaling[J]. PLoS One, 2011, 6(3):e17598. |
| [7] | KüMMEL S, HOLTSCHMIDT J, LOIBL S. Surgical treatment of primary breast cancer in the neoadjuvant setting[J]. Br J Surg, 2014, 101(8):912-924. |
| [8] | BAUM M, DEMICHELI R, HRUSHESKY W, et al. Does surgery unfavourably perturb the natural history of early breast cancer by accelerating the appearance of distant metastases?[J]. Eur J Cancer, 2005, 41(4):508-515. |
| [9] | SHAKHAR G, BEN-ELIYAHU S. Potential prophylactic measures against postoperative immunosuppression: could they reduce recurrence rates in oncological patients[J]? Ann Surg Oncol, 2003, 10(8):972-992. |
| [10] | YANG SC, CHUNG PJ, HO CM, et al. Propofol inhibits superoxide production, elastase release, and chemotaxis in formyl peptide-activated human neutrophils by blocking formyl peptide receptor 1[J]. J Immunol, 2013, 190(12):6511-6519. |
| [11] | NEEMAN E, BEN-ELIYAHU S. Surgery and stress promote cancer metastasis: new outlooks on perioperative mediating mechanisms and immune involvement[J]. Brain Behav Immun, 2013, 30(Suppl):S32-40. |
| [12] | YOELI-LERNER M, YIU GK, RABINOVITZ I, et al. Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT[J]. Mol Cell, 2005, 20(4):539-550. |
| [13] | MELAMED R, BAR-YOSEF S, SHAKHAR G, et al. Suppression of natural killer cell activity and promotion of tumor metastasis by ketamine, thiopental, and halothane, but not by propofol: mediating mechanisms and prophylactic measures[J]. Anesth Analg, 2003, 97(5):1331-1339. |
| [14] | WU KC, YANG ST, HSIA TC, et al. Suppression of cell invasion and migration by propofol are involved in down-regulating matrix metalloproteinase-2 and p38 MAPK signaling in A549 human lung adenocarcinoma epithelial cells[J]. Anticancer Res, 2012, 32(11):4833-4842. |
| [15] | FERLAY J, SHIN HR, BRAY F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008[J]. Int J Cancer, 2010, 127(12):2893-2917. |
| [16] | DESANTIS C, SIEGEL R, BANDI P, et al. Breast cancer statistics, 2011[J]. CA Cancer J Clin, 2011, 61(6):409-418. |
| [17] | 张雅静，林春水，汪威，等. 丙泊酚对荷瘤大鼠肿瘤肺转移及MTA1和Wnt1表达的影响[J]. 南方医科大学学报, 2014, 34(7):1011-1015. |
| [18] | KATSO R, OKKENHAUG K, AHMADI K, et al. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer[J]. Annu Rev Cell Dev Biol, 2001, 17(1):615-675. |
| [19] | YIU GK, TOKER A. NFAT induces breast cancer cell invasion by promoting the induction of cyclooxygenase-2[J]. J Biol Chem, 2006, 281(18):12210-12217. |
| [20] | HUTCHINSON JN, JIN J, CARDIFF RD, et al. Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion[J]. Cancer Res, 2004, 64(9):3171-3178. |
| [21] | EBI H, COSTA C, FABER AC, et al. PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1[J]. Proc Natl Acad Sci USA, 2013, 110(52):21124-21129. |
