PI3K/Akt/mTOR信号转导通路在肝细胞癌发生发展中的作用

俞媛; 陈晓蓉

doi:10.3969/j.issn.1001-5256.2014.09.029

PI3K/Akt/mTOR信号转导通路在肝细胞癌发生发展中的作用

DOI: 10.3969/j.issn.1001-5256.2014.09.029

俞媛,
陈晓蓉

1. 上海市公共卫生临床中心中医科
2. 复旦大学附属公共卫生临床中心

详细信息

中图分类号: R735.7
计量
- 文章访问数: 2959
- HTML全文浏览量: 21
- PDF下载量: 821
- 被引次数: 0
出版历程
- 收稿日期: 2013-12-12
- 出版日期: 2014-09-20

Role of PI3K /Akt /mTOR signaling pathway in hepatocellular carcinoma

Department of Traditional Chinese Medicine, Shanghai Public Health Clinical Center, Public Health Clinical Center Affiliated to Fudan University

摘要

摘要: PI3K/Akt/mTOR信号转导通路可以通过调控基因表达,在肝细胞癌肿瘤细胞生成、增殖、转移和凋亡等过程中发挥重要作用。简述了PI3K/Akt/mTOR信号通路的组成及功能,对PI3K/Akt/mTOR通路在肝细胞癌进程中的作用机制及相关抑制剂的研究进展进行了综述,揭示阻断PI3K/Akt/mTOR通路可以成为肝细胞癌治疗新的靶点方向。
- 癌,肝细胞 /
- 衔接蛋白质类,信号转导 /
- 综述
Abstract: Phosphatidylinositol 3- kinase, Akt, and the mammalian target of rapamycin ( PI3K/Akt/mTOR) signaling pathway is shown to play a key role in the tumorigenesis, proliferation, metastasis, apoptosis, and angiogenesis of hepatocellular carcinoma ( HCC) by regulating gene expression. The components and functions of PI3 K /Akt /mTOR signaling pathway are briefly described, and the research advances in the action mechanism of PI3 K /Akt /mTOR signaling pathway in the progression of HCC and related inhibitors are reviewed. It is disclosed that blocking the PI3 K /Akt /mTOR signaling pathway may become a new therapy for HCC.
- hepatocellular carcinoma /
- adaptor proteins, signal transducing /
- review

HTML全文

参考文献(40)

[1]JIN Y, LI JT.Research progress in related clinical factors and molecular biomarkers for microvascular invasion in hepatocellular carcinoma[J].J Clin Hepatol, 2013, 29 (7) :550-553. (in Chinese) 金赟, 李江涛.肝癌细胞侵犯微血管的临床相关因素及分子标志物的研究进展[J].临床肝胆病杂志, 2013, 29 (7) :550-553.

[2] LLOVET JM.Updated treatment approach to hepatocellular carcinoma[J].J Gastroenterol, 2005, 40 (3) :225-235.

[3] ANDO E, TANAKA M, YAMASHITA F, et al.Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis:analysis of 48 cases[J].Cancer, 2002, 95 (3) :588-595.

[4]ZHANG Y, ZHANG JW, LYU GY, et al.Effects of STAT3 gene silencing and rapamycin on apoptosis in hepatocarcinoma cells[J].Int J Med Sci, 2012, 9 (3) :216-224.

[5] BHASKAR PT, HAY N.The two TORCs and Akt[J].Dev Cell, 2007, 12 (4) :487-502.

[6]ENGELMAN JA.Targeting PI3K signalling in cancer:opportunities, challenges and limitations[J].Nat Rev Cancer, 2009, 9 (8) :550-562.

[7]ENGELMAN JA, LUO J, CANTLEY LC.The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism[J].Nat Rev Genet, 2006, 7 (8) :606-619.

[8]PENE F, CLAESSENS YE, MULLER O, et al.Role of the phosphatedylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma[J].Oncogene, 2002, 21 (43) :6587-6597.

[9] 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 (4) :615-675.

[10] HILL MM, HEMMINGS BA.Inhibition of protein kinase B/Akt implycations for cancer therapy[J].Pharmacol Ther, 2002, 93 (2/3) :243-251.

[11]HUANG J, MANNING BD.The TSC1-TSC2 complex:a molecular switchboard controlling cell growth[J].Biochem J, 2008, 412 (2) :179-190.

[12]WAN X, HELMAN LJ.The biology behind mTOR inhibition in sarcoma[J].Oncologist, 2007, 12 (8) :1007-1018.

[13] JIANG BH, LIU LZ.PI3K/PTEN signaling in angiogenesis and tumorigenesis[J].Adv Cancer Res, 2009, 102:19-65.

[14]MAMANE Y, PETROULAKIS E, LEBACQUER O, et al.mTOR, translation initiation and cancer[J].Oncogene, 2006, 25 (48) :6416-6422.

[15] GUERTIN DA, SABATINI DM.An expanding role for mTOR in cancer[J].Trends Mol Med, 2005, 11 (8) :353-361.

[16]BANUMATHY G, CAIRNS P.Signaling pathways in renal cell carcinoma[J].Cancer Biol Ther, 2010, 10 (7) :658-664.

[17] DURONIN V.The life of a cell:apoptosis regulation by the PI3K/PKB pathway[J].Biochem J, 2008, 415 (3) :333-344.

[18]LIU LX, LIU ZH, JIANG HC, et al.Gene expression profiles of hepatoma cell line HLE[J].World J Gastroenterol, 2003, 9 (4) :683-687.

[19] SUZUKI Y, TOQUENAGA Y.Effects of information and group structure on evolution of altruism:analysis of two-score model by covariance and contextual analyses[J].J Theor Bio, 2005, 232 (2) :191-201.

[20] MICHL P, DOWNWARD J.Mechanisms of disease:PI3K/AKT signaling in gastrointestinal cancers[J].Z Gastroenterol, 2005, 43 (10) :1133-1139.

[21]TUCK AB, HOTA C, WILSON SM, et al.Osteopontin-induced migration of human mammary epithelial cells involves activation of EGF receptor and multiple signal transduction pathways[J].Oncogene, 2003, 22 (8) :1198-1205.

[22] MOTTET D, DUMONT V, DECEACHE Y, et al.Regulation of hypoxia-inducible factor-1 alpha protein level during hypoxic conditions by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta pathway in HepG2 cells[J].J Biol Chem, 2003, 278 (33) :31277-31285.

[23]LIU L, ZHU S, GONG I, et al.K-ras/PI3K-Akt signaling is essential for zebrafish hematopoiesis and angiogenesis[J].PLos One, 2008, 3 (8) :e2850.

[24] GORDAN JD, SIMON MC.Hypoxia-inducible factors:central regulators of the tumor phenotype[J].Curr Opin Genet Dev, 2007, 17 (1) :71-77.

[25]JIANG BH, LIU LI.AKT signaling in regulating angiogenesis[J].Curr Cancer Drug Targets, 2008, 8 (1) :19-26.

[26]MOTTET D, DUMONT V, DECCACHE Y, et al.Regulation of hypoxia-inducible factor-1 alpha protein level during hypoxic conditions by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta pathway in HepG2 cells[J].J Biol Chem, 2003, 278 (33) :31277-31285.

[27]ARSHAM AM, PLAS DR, THOMPSON CB, et al.Akt and hypoxia-inducible factor-1 independently enhance tumor growth and angiogenesis[J].Cancer Res, 2004, 64 (10) :3500-3507.

[28]OHTA T, OHMICHI M, HAYASAKA T, et al.Inhibition of phosphatidylinositol 3-kinase increases efficacy of cisplatin in in vivo ovarian cancer models[J].Endocrinology, 2006, 147 (4) :1761-1769.

[29]GERA JF, MELLINGHOFF IK, SHI Y, et al.AKT activity determines sensitivity to mammalian target of rapamyein (mTOR) inhibitors by regulating cyclin D1 and c-myc expression[J].J Biol Chem, 2004, 279 (4) :2737-2746.

[30]JUNG KH, ZHENG HM, JEONG Y, et al.Suppression of tumor proliferation and angiogenesis of hepatocellular carcinoma by HS-104, a novel phosphoinositide 3-kinase inhibitor[J].Cancer Lett, 2013, 328 (1) :176-187.

[31] CHANG Z, SHI G, JIN J, et al.Dual PI3K/mTOR inhibitor NVP-BEZ235-induced apoptosis of hepatocellular carcinoma cell lines is enhanced byinhibitors of autophagy[J].Int J Mol Med, 2013, 31 (6) :1449-1456.

[32]LEE JH, LEE H, YUN SM, et al.IPD-196, a novel phosphatidylinositol 3-kinase inhibitor with potent anticancer activity against hepatocellular carcinoma[J].Cancer Lett, 2013, 329 (1) :99-108.

[33]SIMIONI C, MARTELLI AM, CANI A, et al.The AKT inhibitor MK-2206 is cytotoxic in hepatocarcinoma cells displaying hyperphosphorylated AKT-1 and synergizes with conventional chemotherapy[J].Oncotarget, 2013, 4 (9) :1496-1506.

[34]MEUILLET EJ, IHLE N, BAKER AF, et al.In vivo molecular pharmacology and antitumor activity of the targeted Akt inhibitor PX-316[J].Oncol Res, 2004, 14 (10) :513-527.

[35] ZHANG M, FANG X, LIU H, et al.Blockade of AKT activation in prostate cancer cells with a small molecule inhibitor, 9-chloro-2-methylellipticinium acetate (CMEP) [J].Biochem Pharmacol, 2007, 73 (1) :15-24.

[36] SEMELA D, PIGUET AC, KOLEV M, et al.Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma[J].J Hepatology, 2007, 46 (5) :840-848.

[37]DANCEY JE.Inhibitors of the mammalian target of rapamycin[J].Expert Opin Investig Drugs, 2005, 14 (3) :313-328.

[38] KNOWLES MA, PLATT FM, ROSS RL, et al.Phosphatidylinositol 3-kinase (PI3K) pathway activation in bladder cancer[J].Cancer Metastasis Rev, 2009, 28 (3-4) :305-316.

[39] KIRSTEIN MM, BOUKOURIS AE, POTHIRAJU D, et al.Activity of the mTOR inhibitor RAD001, the dual mTOR and PI3-kinase inhibitor BEZ235 and the PI3-kinase inhibitor BKM120 in hepatocellular carcinoma[J].Liver Int, 2013, 33 (5) :780-793.

[40]FUEREDER T, JAEGER A, HOEFLMAYER D, et al.mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and improves antitumor activity against gastric cancer in vivo[J].Cancer Lett, 2010, 296 (2) :249-256.引证本文:YU Y, CHEN XR.Role of PI3K/Akt/mTOR signaling pathway in hepatocellular carcinoma[J].J Clin Hepatol, 2014, 30 (9) :954-957. (in Chinese) 俞媛, 陈晓蓉.PI3K/Akt/mTOR信号转导通路在肝细胞癌发生发展中的作用[J].临床肝胆病杂志, 2014, 30 (9) :954-957.

施引文献

资源附件(0)

访问统计