细胞外信号调节激酶与肿瘤的关系及其抑制剂的研究进展
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摘要
细胞外信号调节激酶(ERK)是信号转导通路的重要分子,主要功能是把细胞外的信号通过磷酸化逐级传递至细胞核,参与细胞多种生物学行为。研究表明ERK1/2在肝癌、乳腺癌、前列腺癌以及宫颈癌等多种肿瘤组织和细胞中异常活化或过度表达,与肿瘤的发生发展有关。ERK1/2靶向抑制也成为近年肿瘤治疗的研究热点。本文主要就ERK1/2与肝癌、胃癌、宫颈癌的关系及相关ERK1/2抑制剂的研究进展进行综述。
Extracellular signal-regulated kinase(ERK) is a significant molecule of signal transduction pathway. Its main function is to transfer extracellular signals step by step to the nucleus through phosphorylation and participate in many biological behaviors of cells.Studies have shown that ERK1/2 is abnormally activated or over-expressed in various tumor tissues and cells such as liver cancer, breast cancer, prostate cancer and cervical cancer. Its abnormal molecular activation is related to the occurrence and development of tumors.Therefore, ERK1/2 targeted inhibition has also become a research hotspot in cancer therapy in recent years. This review focuses on the relationship between ERK1/2 and liver cancer, gastric cancer, cervical cancer and the related ERK1/2 inhibitors.
Extracellular signal-regulated kinase(ERK) is a significant molecule of signal transduction pathway. Its main function is to transfer extracellular signals step by step to the nucleus through phosphorylation and participate in many biological behaviors of cells.Studies have shown that ERK1/2 is abnormally activated or over-expressed in various tumor tissues and cells such as liver cancer, breast cancer, prostate cancer and cervical cancer. Its abnormal molecular activation is related to the occurrence and development of tumors.Therefore, ERK1/2 targeted inhibition has also become a research hotspot in cancer therapy in recent years. This review focuses on the relationship between ERK1/2 and liver cancer, gastric cancer, cervical cancer and the related ERK1/2 inhibitors.
引文
[1]Cicenas J, Zalyte E, Rimkus A, et al. JNK, p38, ERK, and SGK1 Inhibitors in Cancer[J]. Cancers, 2017, 10(1):1. doi:10.3390/cancers10010001.
[2]Maik-Rachline G, Seger R. The ERK cascade inhibitors:Towards overcoming resistance[J]. Drug Resist Updat,2016, 25:1-12. doi:10.1016/j. drup.2015.12.001.
[3]Nabet B,óBroin P, Reyes JM, et al. Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape[J]. Cell Rep, 2015, 2(8):1300-1313. doi:10.1016/j. celrep.2015.06.078.
[4]O'Donnell A, Odrowaz Z, Sharrocks AD. Immediate-early gene activation by the MAPK pathways:what do and don't we know?[J]. Biochem Soc Trans, 2012, 40(1):58-66. doi:10.1042/BST20110636.
[5]Blüthgen N, Legewie S. Systems analysis of MAPK signal transduction[J]. Essays Biochem, 2008, 45:95-107. doi:10.1042/BSE0450095.
[6]Cook SJ, Stuart K, Gilley R, et al. Control of cell death and mitochondrial fission by ERK1/2 MAP kinase signalling[J]. FEBS J, 2017, 284(24):4177-4195. doi:10.1111/febs.14122.
[7]Caunt CJ, Sale MJ, Smith PD, et al. MEK1 and MEK2inhibitors and cancer therapy:the long and winding road[J]. Nat Rev Cancer, 2015, 15(10):577-592. doi:10.1038/nrc4000.
[8]ünal EB, Uhlitz F, Blüthgen N. A compendium of ERK targets[J]. FEBS Lett, 2017, 591(17):2607-2615. doi:10.1002/1873-3468.12740.
[9]Kidger AM, Sipthorp J, Cook SJ. ERK1/2 inhibitors:New weapons to inhibit the RAS-regulated RAF-MEK1/2-ERK1/2 pathway[J]. Pharmacol Ther, 2018, 187:45-60.doi:10.1016/j. pharmthera.2018.02.007.
[10]Müller S, Chaikuad A, Gray NS, et al. The ins and outs of selective kinase inhibitor development[J]. Nat Chem Biol,2015, 11(11):818-821. doi:10.1038/nchembio.1938.
[11]Yap J L, Worlikar S, Mackerell A D, et al. ChemInform Abstract:Small-Molecule Inhibitors of the ERK Signaling Pathway:Towards Novel Anticancer Therapeutics[J]. Cheminform, 2011, 42(15):38-48. doi:10.1002/cmdc.201000354。
[12]Hwang YH, Choi JY, Kim S, et al. Over-expression of c-raf-1 proto-oncogene in liver cirrhosis and hepatocellular carcinoma[J]. Hepatol Res, 2004, 29(2):113-121. doi::10.1016/j. hepres.2004.02.009.
[13]Ito Y, Sasaki Y, Horimoto M, et a1. Activation of mitogenactivated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma[J]. Hepatology,1998, 27(4):951-958.
[14]He D, Liu ZP, Honda M, et al. Coexpression network analysis in chronic hepatitis B and C hepatic lesions reveals distinct patterns of disease progression to hepatocellular carcinoma[J]. J Mol Cell Biol, 2012, 4(3):140-152. doi:10.1093/jmcb/mjs011.
[15]Ahamed S, Foster JS, Bukovsky A, et al. Signal transduction through the Ras/Erk pathway is essential for the mycoestrogen zearalenone-induced cell-cycle progression in MCF-7cells[J]. Mol Carcinog, 2001, 30(2):88-98. doi:10.1002/1098-2744(200102)30:2<88::aid-mc1017>3.0. co; 2-e.
[16]Huynh H, Nguyen TT, Chow KH, et al. Over-expression of the mitogen-activated protein kinase(MAPK)kinase(MEK)-MAPK in hepatocellular carcinoma:its role in tumor progression and apoptosis[J]. BMC Gastroenterol, 2003, 3:19.doi:10.1186/1471-230X-3-19.
[17]Masoumi-Moghaddam S, Amini A, Morris DL. The developing story of Sprouty and cancer[J]. Cancer Metastasis Rev, 2014, 33(2-3):695-720. doi:10.1007/s10555-014-9497-1.
[18]O'Neil BH, Goff LW, Kauh JS, et al. Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma[J].J Clin Oncol, 2011, 29(17):2350-2356. doi:10.1200/JCO.2010.33.9432.
[19]黄迪,李飞薄,玉琨,等. GLO1在胃癌组织中的表达研究[J].临床和实验医学杂志, 2015, 14(13):1051-1054.doi:10.3969/j. issn.1671-4695.2015.013.002.
[20]姜浩,孙治国. Raf-1、MEK-2、ERK-1在胃癌组织中的表达及其意义[J].中国现代医生, 2017, 55(15):30-33.
[21]Meng F, Dong B, Li H, et al. RNAi-mediated inhibition of Raf-1 leads to decreased angiogenesis and tumor growth in gastric cancer[J]. Cancer Biol Ther, 2009, 8(2):174-179.doi:10.4161/cbt.8.2.7208.
[22]Zhang Y, Du J, Zheng J, et al. EGF-reduced Wnt5a transcription induces epithelial-mesenchymal transition via Arf6-ERK signaling in gastric cancer cells[J]. Oncotarget,2015, 6(9):7244-7261. doi:10.18632/oncotarget.3133.
[23]Yao J, Qian C, Shu T, et al. Combination treatment of PD98059 and DAPT in gastric cancer through induction of apoptosis and downregulation of WNT/β-catenin[J]. Cancer Biol Ther, 2013, 14(9):833-839. doi:10.4161/cbt.25332.
[24]Hou X, Zhang Y, Qiao H. CCL18 promotes the invasion and migration of gastric cancer cells via ERK1/2/NF-κB signaling pathway[J]. Tumour Biol, 2016, 37(1):641-651. doi:10.1007/s13277-015-3825-0.
[25]Wang X, Yu Z, Zhou Q, et al. Tissue transglutaminase-2promotes gastric cancer progression via the ERK1/2 pathway[J]. Oncotarget, 2016, 7(6):7066-7079. doi:10.18632/oncotarget.6883.
[26]Li P, Jia YF, Ma XL, et al. DEC2 suppresses tumor proliferation and metastasis by regulating ERK/NF-κB pathway in gastric cancer[J]. Am J Cancer Res, 2016, 6(8):1741-1757.doi:
[27]Wu H, Goel V, Haluska FG. PTEN signaling pathways in melanoma[J]. Oncogene, 2003, 22(20):3113-3122. doi:10.1038/sj. onc.1206451.
[28]Zheng ST, Huo Q, Tuerxun A, et al. The expression and activation of ERK/MAPK pathway in human esophageal cancer cell line EC9706[J]. Mol Biol Rep, 2011, 38(2):865-872. doi:10.1007/s11033-010-0178-z.
[29]Cui Y, Li Q, Li H, et al. Asparaginyl endopeptidase improves the resistance of microtubule-targeting drugs in gastric cancer through IQGAP1 modulating the EGFR/JNK/ERK signaling pathway[J]. Onco Targets Ther, 2017, 10:627-643. doi:10.2147/OTT. S125579.
[30]Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015[J]. CA Cancer J Clin, 2015, 65(1):5-29. doi:10.3322/caac.21254.
[31]Yuan H, Ito S, Senga T, et a1. Human papillomavirus type16 oncoprotein E7 suppresses cadherin-mediated cell adhesion via ERK and AP-1 signaling[J]. Int J Oncol, 2009,35(2):309-314.
[32]Liu C, Ding L, Bai L, et al. Folate receptor alpha is associated with cervical carcinogenesis and regulates cervical cancer cells growth by activating ERK1/2/c-Fos/c-Jun[J].Biochem Biophys Res Commun, 2017, 491(4):1083-1091.doi:10.1016/j. bbrc.2017.08.015.
[33]Ramos JW. The regulation of extracellular signal-regulated kinase(ERK)in mammalian cells[J]. Int J Biochem Cell Biol, 2008, 40(12):2707-2719. doi:10.1016/j. biocel.2008.04.009.
[34]Engelbrecht AM, Gebhardt S, Louw L. Ex vivo study of MAPK profiles correlated with parameters of apoptosis during cervical carcinogenesis[J]. Cancer Lett, 2006, 235(1):93-99. doi:10.1016/j. canlet.2005.04.005.
[35]Kim SH, Kim SH, Kim YB, et al. Genistein inhibits cell growth by modulating various mitogen-activated protein kinases and AKT in cervical cancer cells[J]. Ann N Y Acad Sci, 2009, 1171:495-500. doi:10.1111/j.1749-6632.2009.04899. x.
[36]章丽霞,刘钧.细胞外信号调节激酶(ERK)与宫颈癌关系的研究进展[J].川北医学院学报, 2010, 25(5):478-482. doi:10.3969/j. issn.1005-3697.2010.05.029.
[37]Jia L, Li F, Shao M, et al. IL-8 is upregulated in cervical cancer tissues and is associated with the proliferation and migration of HeLa cervical cancer cells[J]. Oncol Lett,2018, 15(1):1350-1356. doi:10.3892/ol.2017.7391.
[38]Liu SQ, Yu JP, Yu HG, et al. Activation of Akt and ERK signalling pathways induced by etoposide confer chemoresistance in gastric cancer cells[J]. Dig Liver Dis, 2006,38(5):310-318. doi:10.1016/j. dld.2006.01.012.
[39]Liu T, Liu Y, Bao X, et al. Overexpression of TROP2 predicts poor prognosis of patients with cervical cancer and promotes the proliferation and invasion of cervical cancer cells by regulating ERK signaling pathway[J]. PLoS One,2013, 8(9):e75864. doi:10.1371/journal. pone.0075864.
[40]Poto?njak I, Gobin I, Domitrovi?R. Carvacrol induces cytotoxicity in human cervical cancer cells but causes cisplatin resistance:Involvement of MEK-ERK activation[J]. Phytother Res, 2018, 32(6):1090-1097. doi:10.1002/ptr.6048.
[2]Maik-Rachline G, Seger R. The ERK cascade inhibitors:Towards overcoming resistance[J]. Drug Resist Updat,2016, 25:1-12. doi:10.1016/j. drup.2015.12.001.
[3]Nabet B,óBroin P, Reyes JM, et al. Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape[J]. Cell Rep, 2015, 2(8):1300-1313. doi:10.1016/j. celrep.2015.06.078.
[4]O'Donnell A, Odrowaz Z, Sharrocks AD. Immediate-early gene activation by the MAPK pathways:what do and don't we know?[J]. Biochem Soc Trans, 2012, 40(1):58-66. doi:10.1042/BST20110636.
[5]Blüthgen N, Legewie S. Systems analysis of MAPK signal transduction[J]. Essays Biochem, 2008, 45:95-107. doi:10.1042/BSE0450095.
[6]Cook SJ, Stuart K, Gilley R, et al. Control of cell death and mitochondrial fission by ERK1/2 MAP kinase signalling[J]. FEBS J, 2017, 284(24):4177-4195. doi:10.1111/febs.14122.
[7]Caunt CJ, Sale MJ, Smith PD, et al. MEK1 and MEK2inhibitors and cancer therapy:the long and winding road[J]. Nat Rev Cancer, 2015, 15(10):577-592. doi:10.1038/nrc4000.
[8]ünal EB, Uhlitz F, Blüthgen N. A compendium of ERK targets[J]. FEBS Lett, 2017, 591(17):2607-2615. doi:10.1002/1873-3468.12740.
[9]Kidger AM, Sipthorp J, Cook SJ. ERK1/2 inhibitors:New weapons to inhibit the RAS-regulated RAF-MEK1/2-ERK1/2 pathway[J]. Pharmacol Ther, 2018, 187:45-60.doi:10.1016/j. pharmthera.2018.02.007.
[10]Müller S, Chaikuad A, Gray NS, et al. The ins and outs of selective kinase inhibitor development[J]. Nat Chem Biol,2015, 11(11):818-821. doi:10.1038/nchembio.1938.
[11]Yap J L, Worlikar S, Mackerell A D, et al. ChemInform Abstract:Small-Molecule Inhibitors of the ERK Signaling Pathway:Towards Novel Anticancer Therapeutics[J]. Cheminform, 2011, 42(15):38-48. doi:10.1002/cmdc.201000354。
[12]Hwang YH, Choi JY, Kim S, et al. Over-expression of c-raf-1 proto-oncogene in liver cirrhosis and hepatocellular carcinoma[J]. Hepatol Res, 2004, 29(2):113-121. doi::10.1016/j. hepres.2004.02.009.
[13]Ito Y, Sasaki Y, Horimoto M, et a1. Activation of mitogenactivated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma[J]. Hepatology,1998, 27(4):951-958.
[14]He D, Liu ZP, Honda M, et al. Coexpression network analysis in chronic hepatitis B and C hepatic lesions reveals distinct patterns of disease progression to hepatocellular carcinoma[J]. J Mol Cell Biol, 2012, 4(3):140-152. doi:10.1093/jmcb/mjs011.
[15]Ahamed S, Foster JS, Bukovsky A, et al. Signal transduction through the Ras/Erk pathway is essential for the mycoestrogen zearalenone-induced cell-cycle progression in MCF-7cells[J]. Mol Carcinog, 2001, 30(2):88-98. doi:10.1002/1098-2744(200102)30:2<88::aid-mc1017>3.0. co; 2-e.
[16]Huynh H, Nguyen TT, Chow KH, et al. Over-expression of the mitogen-activated protein kinase(MAPK)kinase(MEK)-MAPK in hepatocellular carcinoma:its role in tumor progression and apoptosis[J]. BMC Gastroenterol, 2003, 3:19.doi:10.1186/1471-230X-3-19.
[17]Masoumi-Moghaddam S, Amini A, Morris DL. The developing story of Sprouty and cancer[J]. Cancer Metastasis Rev, 2014, 33(2-3):695-720. doi:10.1007/s10555-014-9497-1.
[18]O'Neil BH, Goff LW, Kauh JS, et al. Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma[J].J Clin Oncol, 2011, 29(17):2350-2356. doi:10.1200/JCO.2010.33.9432.
[19]黄迪,李飞薄,玉琨,等. GLO1在胃癌组织中的表达研究[J].临床和实验医学杂志, 2015, 14(13):1051-1054.doi:10.3969/j. issn.1671-4695.2015.013.002.
[20]姜浩,孙治国. Raf-1、MEK-2、ERK-1在胃癌组织中的表达及其意义[J].中国现代医生, 2017, 55(15):30-33.
[21]Meng F, Dong B, Li H, et al. RNAi-mediated inhibition of Raf-1 leads to decreased angiogenesis and tumor growth in gastric cancer[J]. Cancer Biol Ther, 2009, 8(2):174-179.doi:10.4161/cbt.8.2.7208.
[22]Zhang Y, Du J, Zheng J, et al. EGF-reduced Wnt5a transcription induces epithelial-mesenchymal transition via Arf6-ERK signaling in gastric cancer cells[J]. Oncotarget,2015, 6(9):7244-7261. doi:10.18632/oncotarget.3133.
[23]Yao J, Qian C, Shu T, et al. Combination treatment of PD98059 and DAPT in gastric cancer through induction of apoptosis and downregulation of WNT/β-catenin[J]. Cancer Biol Ther, 2013, 14(9):833-839. doi:10.4161/cbt.25332.
[24]Hou X, Zhang Y, Qiao H. CCL18 promotes the invasion and migration of gastric cancer cells via ERK1/2/NF-κB signaling pathway[J]. Tumour Biol, 2016, 37(1):641-651. doi:10.1007/s13277-015-3825-0.
[25]Wang X, Yu Z, Zhou Q, et al. Tissue transglutaminase-2promotes gastric cancer progression via the ERK1/2 pathway[J]. Oncotarget, 2016, 7(6):7066-7079. doi:10.18632/oncotarget.6883.
[26]Li P, Jia YF, Ma XL, et al. DEC2 suppresses tumor proliferation and metastasis by regulating ERK/NF-κB pathway in gastric cancer[J]. Am J Cancer Res, 2016, 6(8):1741-1757.doi:
[27]Wu H, Goel V, Haluska FG. PTEN signaling pathways in melanoma[J]. Oncogene, 2003, 22(20):3113-3122. doi:10.1038/sj. onc.1206451.
[28]Zheng ST, Huo Q, Tuerxun A, et al. The expression and activation of ERK/MAPK pathway in human esophageal cancer cell line EC9706[J]. Mol Biol Rep, 2011, 38(2):865-872. doi:10.1007/s11033-010-0178-z.
[29]Cui Y, Li Q, Li H, et al. Asparaginyl endopeptidase improves the resistance of microtubule-targeting drugs in gastric cancer through IQGAP1 modulating the EGFR/JNK/ERK signaling pathway[J]. Onco Targets Ther, 2017, 10:627-643. doi:10.2147/OTT. S125579.
[30]Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015[J]. CA Cancer J Clin, 2015, 65(1):5-29. doi:10.3322/caac.21254.
[31]Yuan H, Ito S, Senga T, et a1. Human papillomavirus type16 oncoprotein E7 suppresses cadherin-mediated cell adhesion via ERK and AP-1 signaling[J]. Int J Oncol, 2009,35(2):309-314.
[32]Liu C, Ding L, Bai L, et al. Folate receptor alpha is associated with cervical carcinogenesis and regulates cervical cancer cells growth by activating ERK1/2/c-Fos/c-Jun[J].Biochem Biophys Res Commun, 2017, 491(4):1083-1091.doi:10.1016/j. bbrc.2017.08.015.
[33]Ramos JW. The regulation of extracellular signal-regulated kinase(ERK)in mammalian cells[J]. Int J Biochem Cell Biol, 2008, 40(12):2707-2719. doi:10.1016/j. biocel.2008.04.009.
[34]Engelbrecht AM, Gebhardt S, Louw L. Ex vivo study of MAPK profiles correlated with parameters of apoptosis during cervical carcinogenesis[J]. Cancer Lett, 2006, 235(1):93-99. doi:10.1016/j. canlet.2005.04.005.
[35]Kim SH, Kim SH, Kim YB, et al. Genistein inhibits cell growth by modulating various mitogen-activated protein kinases and AKT in cervical cancer cells[J]. Ann N Y Acad Sci, 2009, 1171:495-500. doi:10.1111/j.1749-6632.2009.04899. x.
[36]章丽霞,刘钧.细胞外信号调节激酶(ERK)与宫颈癌关系的研究进展[J].川北医学院学报, 2010, 25(5):478-482. doi:10.3969/j. issn.1005-3697.2010.05.029.
[37]Jia L, Li F, Shao M, et al. IL-8 is upregulated in cervical cancer tissues and is associated with the proliferation and migration of HeLa cervical cancer cells[J]. Oncol Lett,2018, 15(1):1350-1356. doi:10.3892/ol.2017.7391.
[38]Liu SQ, Yu JP, Yu HG, et al. Activation of Akt and ERK signalling pathways induced by etoposide confer chemoresistance in gastric cancer cells[J]. Dig Liver Dis, 2006,38(5):310-318. doi:10.1016/j. dld.2006.01.012.
[39]Liu T, Liu Y, Bao X, et al. Overexpression of TROP2 predicts poor prognosis of patients with cervical cancer and promotes the proliferation and invasion of cervical cancer cells by regulating ERK signaling pathway[J]. PLoS One,2013, 8(9):e75864. doi:10.1371/journal. pone.0075864.
[40]Poto?njak I, Gobin I, Domitrovi?R. Carvacrol induces cytotoxicity in human cervical cancer cells but causes cisplatin resistance:Involvement of MEK-ERK activation[J]. Phytother Res, 2018, 32(6):1090-1097. doi:10.1002/ptr.6048.