内质网应激PERK通路在肿瘤中的研究进展
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摘要
肿瘤细胞在生长、浸润和转移过程中经历的缺氧、低糖等多种环境压力会对肿瘤细胞造成内质网应激,为应对内质网应激,肿瘤细胞会诱发未折叠蛋白反应(Unfolded protein response,UPR)。PERK通路作为激活UPR的一条关键通路可通过提高肿瘤对不良微环境的耐受程度、诱导新生血管生成、诱导自噬体形成、激活凋亡信号分子等促进肿瘤细胞生长、增殖、侵袭及保护性自噬,并且在UPR达到一定程度时诱导肿瘤细胞凋亡及自噬性死亡。
During growth,invasion and metastasis,tumor cells undergo endoplasmic reticulum stress( ERS) under hypoxia,hypoglycemia and other environmental stresses. In response to ERS,tumor cells induce unfolded protein response( UPR). PERK signaling pathway as a key pathway to activate UPR can promote survival,proliferation,invasion and protection of tumor cells by increasing tumor tolerance to adverse microenvironment,inducting angiogenesis,inducing autophagosome formation and activating apoptotic signal molecules. Tumor cells are induced apoptotic and autophagic death when UPR reaches a certain extent.
During growth,invasion and metastasis,tumor cells undergo endoplasmic reticulum stress( ERS) under hypoxia,hypoglycemia and other environmental stresses. In response to ERS,tumor cells induce unfolded protein response( UPR). PERK signaling pathway as a key pathway to activate UPR can promote survival,proliferation,invasion and protection of tumor cells by increasing tumor tolerance to adverse microenvironment,inducting angiogenesis,inducing autophagosome formation and activating apoptotic signal molecules. Tumor cells are induced apoptotic and autophagic death when UPR reaches a certain extent.
引文
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2 Singleton DC,Harris AL.Targeting the ATF4 pathway in cancer therapy[J].Expert Opin Ther Targets,2012,16(12):1189-1202.
3 Koromilas AE.Roles of the translation initiation factor e IF2alpha serine 51 phosphorylation in cancer formation and treatment[J].Biochim Biophys Acta,2015,1849(7):871-880.
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7 胡亚玲.葡萄糖剥夺通过上调ATF4诱导结直肠癌耐药的实验研究[D].江苏:江南大学,2016.
8 Pyo CW,Choi JH,Oh SM,et al.Oxidative stress-induced cyclin D1 depletion and its role in cell cycle processing[J].Biochim Biophys Acta,2013,1830(11):5316-5325.
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13 Sanda GM,Deleanu M,Toma L,et al.Oxidized LDL-exposed human macrophages display increased MMP-9 expression and secretion mediated by endoplasmic reticulum stress[J].J Cell Biochem,2017,118(4):661-669.
14 Feng YX,Sokol ES,Del Vecchio CA,et al.Epithelial-to-mesenchymal transition activates PERK-e IF2alpha and sensitizes cells to endoplasmic reticulum stress[J].Cancer Discov,2014,4(6):702-715.
15 Verfaillie T,Garg AD,Agostinis P.Targeting ER stress induced apoptosis and inflammation in cancer[J].Cancer Lett,2013,332(2):249-264.
16 Li Y,Guo Y,Tang J,et al.New insights into the roles of CHOP-induced apoptosis in ER stress[J].Acta Biochim Biophys Sin,2015,47(2):146-147.
17 李晓娟,夏榕蔓,楼招欢,等.丹参二萜醌通过PERKEIF2α通路诱导肺癌PC9细胞凋亡的机制研究[J].中华中医药杂志,2017,32(5):1897-1902.
18 Hiramatsu N,Messah C,Han J,et al.Translational and posttranslational regulation of XIAP by e IF2alpha and ATF4 promotes ER stress-induced cell death during the unfolded protein response[J].Mol Biol Cell,2014,25(9):1411-1420.
19 Kroemer G,Marino G,Levine B.Autophagy and the integrated stress response[J].Mol Cell,2010,40(2):280-293.
20 Kania E,Pajak B,Orzechowski A.Calcium homeostasis and ER stress in control of autophagy in cancer cells[J].Biomed Res Int,2015,2015:1-12.
21 Kouroku Y,Fujita E,Tanida I,et al.ER stress(PERK/e IF2alpha phosphorylation)mediates the polyglutamineinduced LC3 conversion,an essential step for autophagy formation[J].Cell Death Differ,2007,14(2):230-239.
22 Hasanain M,Bhattacharjee A,Pandey P,et al.A-Solanine induces ROS-mediated autophagy through activation of endoplasmic reticulum stress and inhibition of Akt/m TOR pathway[J].Cell Death Dis,2015,6:e1860.
23 Hart LS,Cunningham JT,Datta T,et al.ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth[J].J Clin Invest,2012,122(12):4621-4634.
24 Suh DH,Kim MK,Kim HS,et al.Unfolded protein response to autophagy as a promising druggable target for anticancer therapy[J].Ann N Y Acad Sci,2012,1271:20-32.
25 Ma J,Yang YR,Chen W,et al.Fluoxetine synergizes with temozolomide to induce the CHOP-dependent endoplasmic reticulum stress-related apoptosis pathway in glioma cells[J].Oncol Rep,2016,36(2):676-684.
26 Atkins C,Liu Q,Minthorn E,et al.Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity[J].Cancer Res,2013,73(6):1993-2002.
27 Axten JM,Medina JR,Feng Y,et al.Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3 -d]pyrimidin-4-amine(GSK2606414),a potent and selective first-in-class inhibitor of protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)[J].J Med Chem,2012,55(16):7193-207.
28 Nagelkerke A,Bussink J,Van Der Kogel AJ,et al.The PERK/ATF4/LAMP3-arm of the unfolded protein response affects radioresistance by interfering with the DNA damage response[J].Radiother Oncol,2013,108(3):415-421.
2 Singleton DC,Harris AL.Targeting the ATF4 pathway in cancer therapy[J].Expert Opin Ther Targets,2012,16(12):1189-1202.
3 Koromilas AE.Roles of the translation initiation factor e IF2alpha serine 51 phosphorylation in cancer formation and treatment[J].Biochim Biophys Acta,2015,1849(7):871-880.
4 Bi M,Naczki C,Koritzinsky M,et al.ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth[J].EMBO J,2005,24(19):3470-3481.
5 Martinon F.Targeting endoplasmic reticulum signaling pathways in cancer[J].Acta Oncol,2012,51(7):822-830.
6 Zheng Q,Ye J,Cao J.Translational regulator e IF2alpha in tumor[J].Tumour Biol,2014,35(7):6255-6264.
7 胡亚玲.葡萄糖剥夺通过上调ATF4诱导结直肠癌耐药的实验研究[D].江苏:江南大学,2016.
8 Pyo CW,Choi JH,Oh SM,et al.Oxidative stress-induced cyclin D1 depletion and its role in cell cycle processing[J].Biochim Biophys Acta,2013,1830(11):5316-5325.
9 Han KS,Li N,Raven PA,et al.Inhibition of endoplasmic reticulum chaperone protein glucose-regulated protein 78potentiates anti-angiogenic therapy in renal cell carcinoma through inactivation of the PERK/e IF2alpha pathway[J].Oncotarget,2015,6(33):34818-34830.
10 Chevet E,Hetz C,Samali A.Endoplasmic reticulum stress-activated cell reprogramming in oncogenesis[J].Cancer Discov,2015,5(6):586-597.
11 Dejeans N,Barroso K,Fernandez-Zapico ME,et al.Novel roles of the unfolded protein response in the control of tumor development and aggressiveness[J].Semin Cancer Biol,2015,33:67-73.
12 Manie SN,Lebeau J,Chevet E.Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease.3 .orchestrating the unfolded protein response in oncogenesis:an update[J].Am J Physiol Cell Physiol,2014,307(10):901-907.
13 Sanda GM,Deleanu M,Toma L,et al.Oxidized LDL-exposed human macrophages display increased MMP-9 expression and secretion mediated by endoplasmic reticulum stress[J].J Cell Biochem,2017,118(4):661-669.
14 Feng YX,Sokol ES,Del Vecchio CA,et al.Epithelial-to-mesenchymal transition activates PERK-e IF2alpha and sensitizes cells to endoplasmic reticulum stress[J].Cancer Discov,2014,4(6):702-715.
15 Verfaillie T,Garg AD,Agostinis P.Targeting ER stress induced apoptosis and inflammation in cancer[J].Cancer Lett,2013,332(2):249-264.
16 Li Y,Guo Y,Tang J,et al.New insights into the roles of CHOP-induced apoptosis in ER stress[J].Acta Biochim Biophys Sin,2015,47(2):146-147.
17 李晓娟,夏榕蔓,楼招欢,等.丹参二萜醌通过PERKEIF2α通路诱导肺癌PC9细胞凋亡的机制研究[J].中华中医药杂志,2017,32(5):1897-1902.
18 Hiramatsu N,Messah C,Han J,et al.Translational and posttranslational regulation of XIAP by e IF2alpha and ATF4 promotes ER stress-induced cell death during the unfolded protein response[J].Mol Biol Cell,2014,25(9):1411-1420.
19 Kroemer G,Marino G,Levine B.Autophagy and the integrated stress response[J].Mol Cell,2010,40(2):280-293.
20 Kania E,Pajak B,Orzechowski A.Calcium homeostasis and ER stress in control of autophagy in cancer cells[J].Biomed Res Int,2015,2015:1-12.
21 Kouroku Y,Fujita E,Tanida I,et al.ER stress(PERK/e IF2alpha phosphorylation)mediates the polyglutamineinduced LC3 conversion,an essential step for autophagy formation[J].Cell Death Differ,2007,14(2):230-239.
22 Hasanain M,Bhattacharjee A,Pandey P,et al.A-Solanine induces ROS-mediated autophagy through activation of endoplasmic reticulum stress and inhibition of Akt/m TOR pathway[J].Cell Death Dis,2015,6:e1860.
23 Hart LS,Cunningham JT,Datta T,et al.ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth[J].J Clin Invest,2012,122(12):4621-4634.
24 Suh DH,Kim MK,Kim HS,et al.Unfolded protein response to autophagy as a promising druggable target for anticancer therapy[J].Ann N Y Acad Sci,2012,1271:20-32.
25 Ma J,Yang YR,Chen W,et al.Fluoxetine synergizes with temozolomide to induce the CHOP-dependent endoplasmic reticulum stress-related apoptosis pathway in glioma cells[J].Oncol Rep,2016,36(2):676-684.
26 Atkins C,Liu Q,Minthorn E,et al.Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity[J].Cancer Res,2013,73(6):1993-2002.
27 Axten JM,Medina JR,Feng Y,et al.Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3 -d]pyrimidin-4-amine(GSK2606414),a potent and selective first-in-class inhibitor of protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)[J].J Med Chem,2012,55(16):7193-207.
28 Nagelkerke A,Bussink J,Van Der Kogel AJ,et al.The PERK/ATF4/LAMP3-arm of the unfolded protein response affects radioresistance by interfering with the DNA damage response[J].Radiother Oncol,2013,108(3):415-421.