• 哈爾濱醫(yī)科大學(xué)第二附屬醫(yī)院普外六肝膽外科(黑龍江哈爾濱 150000);

目的  了解調(diào)節(jié)內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)抑制腫瘤細(xì)胞自噬的研究進(jìn)展。
方法  對(duì)國(guó)內(nèi)外有關(guān)內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)抑制腫瘤細(xì)胞自噬的文獻(xiàn)進(jìn)行綜述。
結(jié)果  在Ca2+釋放及未折疊蛋白聚集而誘發(fā)的內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)中,自噬可被多種通路激活,并調(diào)節(jié)生理及病理過(guò)程。
結(jié)論  在腫瘤細(xì)胞內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)中,調(diào)節(jié)其反應(yīng)通路因子進(jìn)而抑制自噬的發(fā)生仍需進(jìn)一步研究。

引用本文: 田浩,韓卓越,代景友,張新晨. 調(diào)節(jié)內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)抑制腫瘤細(xì)胞自噬的研究進(jìn)展. 中國(guó)普外基礎(chǔ)與臨床雜志, 2012, 19(4): 452-455. doi: 復(fù)制

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4. Yorimitsu T, Klionsky DJ. Autophagy: molecular machinery for self-eating [J]. Cell Death Differ, 2005, 12(Suppl 2): 1542-1552.
5. Singh R, Kaushik S, Wang Y, et al. Autophagy regulates lipid metabolism [J]. Nature, 2009, 458(7242): 1131-1135.
6. Li J, Ni M, Lee B, et al. The unfolded protein response regulator GRP78/BiP is required for endoplasmic reticulum integrity and stress-induced autophagy in mammalian cells [J]. Cell DeathDiffer, 2008, 15(9): 1460-1471.
7. Ogata M, Hino S, Saito A, et al. Autophagy is activated for cell survival after endoplasmic reticulum stress [J]. Mol Cell Biol,2006, 26(24): 9220-9231.
8. Kouroku Y, Fujita E, Tanida I, et al. ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation [J]. Cell Death Differ, 2007, 14(2): 230-239.
9. Kim KW, Moretti L, Mitchell LR, et al. Endoplasmic reticulum stress mediates radiation-induced autophagy by perk-eIF2 alpha in caspase-3/7-deficient cells [J]. Oncogene, 2010, 29(22): 3241-3251.
10. Rutkowski DT, Kaufman RJ. All roads Lead to ATF4 [J]. Dev Cell, 2003, 4(4): 442-444.
11. Tallóczy Z, Jiang W, Virgin HW 4th, et al. Regulation of starvation and virus-induced autophagy by the eIF2alpha kinase signaling pathway [J]. Proc Natl Acad Sci USA, 2002, 99(1): 190-195.
12. Carra S, Brunsting JF, Lambert H, et al. HspB8 participates in protein quality control by a non-chaperone-like mechanism that requires eIF2 alpha phosphorylation [J]. J Biol Chem, 2009,284(9): 5523-5532.
13. Qiu W, Zhang J, Dekker MJ, et al. Hepatic autophagy mediates endoplasmic reticulum stress-induced degradation of misfolded apolipoprotein B [J]. Hepatology, 2011, 53(5): 1515-1525.
14. Calfon M, Zeng HQ, Urano F, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA [J]. Nature, 2002, 415(6867): 92-96.
15. Lee AH, Chu GC, Iwakoshi NN, et al. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands [J].EMBO J, 2005, 24(24): 4368-4380.
16. Hetz C, Thielen P, Matus S, et al. XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy [J]. Genes Dev, 2009, 23(19): 2294-2306.
17. Shimizu S, Konishi A, Nishida Y, et al. Involvement of JNK in the regulation of autophagic cell death [J]. Oncogene, 2010,29(14): 2070-2082.
18. Xu P, Das M, Reilly J, et al. JNK regulates FoxO-dependent autophagy in neurons [J]. Genes Dev, 2011, 25(4): 310-322.
19. Mathew R, Karp CM, Beaudoin B, et al. Autophagy suppresses tumorigenesis through elimination of p62 [J]. Cell, 2009,137(6): 1062-1075.
20. Park KJ, Lee SH, Lee CH, et al. Upregulation of beclin-1 expression and phosphorylation of Bcl-2 and p53 are involved in the JNK-mediated autophagic cell death [J]. Biochem Biophys Res Commun, 2009, 382(4): 726-729.
21. Duan WJ, Li QS, Xia MY, et al. Silibinin activated p53 and induced autophagic death in human fibrosarcoma HT1080 cells via reactive oxygen species-p38 and c-Jun N-terminal kinase pathways[J]. Biol Pharm Bull, 2011, 34(1): 47-53.
22. Li DD, Wang LL, Deng R, et al. The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells [J]. Oncogene, 2009,28(6): 886-898.
23. Kim MJ, Woo SJ, Yoon CH, et al. Involvement of autophagy in oncogenic K-Ras-induced malignant cell transformation [J]. J Biol Chem, 2011, 286(15): 12924-12932.
24. Ding WX, Ni HM, Gao W, et al. Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability [J]. Am J Pathol,2007, 171(2): 513-524.
25. Komiya K, Uchida T, Ueno T, et al. Free fatty acids stimulate autophagy in pancreatic β-cells via JNK pathway [J]. Biochem Biophys Res Commun, 2010, 401(4): 561-567.
26. Høyer-Hansen M, Bastholm L, Szyniarowski P, et al. Control of macroautophagy by Calcium, Calmodulin-Dependent kinase Kinase-β, and Bcl-2 [J]. Mol Cell, 2007, 25(2): 193-205.
27. Hardie DG. AMPK: a key regulator of energy balance in the single cell and the whole organism [J]. Int J Obes, 2008, 32 Suppl 4: S7-S12.
28. Herrero-Martín G, Høyer-Hansen M, García-García C, et al. TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells [J]. EMBO J, 2009, 28(6): 677-685.
29. Budanov AV, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling [J]. Cell, 2008,134(3): 451-460.
30. Grotemeier A, Alers S, Pfisterer SG, et al. AMPK-independent induction of autophagy by cytosolic Ca2+ increase [J]. Cell Signal,2010, 22(6): 914-925.
31. Bialik S, Kimchi A. The death-associated protein kinases: structure,function, and beyond [J]. Annu Rev Biochem, 2006, 75:189-210.
32. Zalckvar E, Berissi H, Mizrachy L, et al. DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy [J].EMBO Rep, 2009, 10(3): 285-292.
33. Gozuacik D, Bialik S, Raveh T, et al. DAP-kinase is a mediator of endoplasmic reticulum stress-induced caspase activation and autophagic cell death [J]. Cell Death Differ, 2008, 15(12):1875-1886.
34. Sakaki K, Wu J, Kaufman RJ. Protein kinase Ctheta is required for autophagy in response to stress in the endoplasmic reticulum [J]. J Biol Chem, 2008, 283(22): 15370-15380.
35. Vicencio JM, Ortiz C, Criollo A, et al. The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1 [J]. Cell Death Differ, 2009, 16(7): 1006-1017.
36. Vicencio JM, Lavandero S, Szabadkai G. Ca2 +, autophagy and protein degradation: thrown off balance in neurodegenerative disease [J]. Cell Calcium, 2010, 47(2): 112-121.
37. Wojcikiewicz RJ, Pearce MM, Sliter DA, et al. When worlds collide: IP(3) receptors and the ERAD pathway [J]. Cell Calcium,2009, 46(3): 147-153.
  1. 1. Yorimitsu T, Klionsky DJ. Endoplasmic reticulum stress: a new pathway to induce autophagy [J]. Autophagy, 2007, 3(2): 160-162.
  2. 2. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy [J]. Annu Rev Genet, 2009, 43: 67-93.
  3. 3. De Duve C, Wattiaux R. Functions of lysosomes [J]. Annual review of physiology, 1966, 28: 435-492.
  4. 4. Yorimitsu T, Klionsky DJ. Autophagy: molecular machinery for self-eating [J]. Cell Death Differ, 2005, 12(Suppl 2): 1542-1552.
  5. 5. Singh R, Kaushik S, Wang Y, et al. Autophagy regulates lipid metabolism [J]. Nature, 2009, 458(7242): 1131-1135.
  6. 6. Li J, Ni M, Lee B, et al. The unfolded protein response regulator GRP78/BiP is required for endoplasmic reticulum integrity and stress-induced autophagy in mammalian cells [J]. Cell DeathDiffer, 2008, 15(9): 1460-1471.
  7. 7. Ogata M, Hino S, Saito A, et al. Autophagy is activated for cell survival after endoplasmic reticulum stress [J]. Mol Cell Biol,2006, 26(24): 9220-9231.
  8. 8. Kouroku Y, Fujita E, Tanida I, et al. ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation [J]. Cell Death Differ, 2007, 14(2): 230-239.
  9. 9. Kim KW, Moretti L, Mitchell LR, et al. Endoplasmic reticulum stress mediates radiation-induced autophagy by perk-eIF2 alpha in caspase-3/7-deficient cells [J]. Oncogene, 2010, 29(22): 3241-3251.
  10. 10. Rutkowski DT, Kaufman RJ. All roads Lead to ATF4 [J]. Dev Cell, 2003, 4(4): 442-444.
  11. 11. Tallóczy Z, Jiang W, Virgin HW 4th, et al. Regulation of starvation and virus-induced autophagy by the eIF2alpha kinase signaling pathway [J]. Proc Natl Acad Sci USA, 2002, 99(1): 190-195.
  12. 12. Carra S, Brunsting JF, Lambert H, et al. HspB8 participates in protein quality control by a non-chaperone-like mechanism that requires eIF2 alpha phosphorylation [J]. J Biol Chem, 2009,284(9): 5523-5532.
  13. 13. Qiu W, Zhang J, Dekker MJ, et al. Hepatic autophagy mediates endoplasmic reticulum stress-induced degradation of misfolded apolipoprotein B [J]. Hepatology, 2011, 53(5): 1515-1525.
  14. 14. Calfon M, Zeng HQ, Urano F, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA [J]. Nature, 2002, 415(6867): 92-96.
  15. 15. Lee AH, Chu GC, Iwakoshi NN, et al. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands [J].EMBO J, 2005, 24(24): 4368-4380.
  16. 16. Hetz C, Thielen P, Matus S, et al. XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy [J]. Genes Dev, 2009, 23(19): 2294-2306.
  17. 17. Shimizu S, Konishi A, Nishida Y, et al. Involvement of JNK in the regulation of autophagic cell death [J]. Oncogene, 2010,29(14): 2070-2082.
  18. 18. Xu P, Das M, Reilly J, et al. JNK regulates FoxO-dependent autophagy in neurons [J]. Genes Dev, 2011, 25(4): 310-322.
  19. 19. Mathew R, Karp CM, Beaudoin B, et al. Autophagy suppresses tumorigenesis through elimination of p62 [J]. Cell, 2009,137(6): 1062-1075.
  20. 20. Park KJ, Lee SH, Lee CH, et al. Upregulation of beclin-1 expression and phosphorylation of Bcl-2 and p53 are involved in the JNK-mediated autophagic cell death [J]. Biochem Biophys Res Commun, 2009, 382(4): 726-729.
  21. 21. Duan WJ, Li QS, Xia MY, et al. Silibinin activated p53 and induced autophagic death in human fibrosarcoma HT1080 cells via reactive oxygen species-p38 and c-Jun N-terminal kinase pathways[J]. Biol Pharm Bull, 2011, 34(1): 47-53.
  22. 22. Li DD, Wang LL, Deng R, et al. The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells [J]. Oncogene, 2009,28(6): 886-898.
  23. 23. Kim MJ, Woo SJ, Yoon CH, et al. Involvement of autophagy in oncogenic K-Ras-induced malignant cell transformation [J]. J Biol Chem, 2011, 286(15): 12924-12932.
  24. 24. Ding WX, Ni HM, Gao W, et al. Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability [J]. Am J Pathol,2007, 171(2): 513-524.
  25. 25. Komiya K, Uchida T, Ueno T, et al. Free fatty acids stimulate autophagy in pancreatic β-cells via JNK pathway [J]. Biochem Biophys Res Commun, 2010, 401(4): 561-567.
  26. 26. Høyer-Hansen M, Bastholm L, Szyniarowski P, et al. Control of macroautophagy by Calcium, Calmodulin-Dependent kinase Kinase-β, and Bcl-2 [J]. Mol Cell, 2007, 25(2): 193-205.
  27. 27. Hardie DG. AMPK: a key regulator of energy balance in the single cell and the whole organism [J]. Int J Obes, 2008, 32 Suppl 4: S7-S12.
  28. 28. Herrero-Martín G, Høyer-Hansen M, García-García C, et al. TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells [J]. EMBO J, 2009, 28(6): 677-685.
  29. 29. Budanov AV, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling [J]. Cell, 2008,134(3): 451-460.
  30. 30. Grotemeier A, Alers S, Pfisterer SG, et al. AMPK-independent induction of autophagy by cytosolic Ca2+ increase [J]. Cell Signal,2010, 22(6): 914-925.
  31. 31. Bialik S, Kimchi A. The death-associated protein kinases: structure,function, and beyond [J]. Annu Rev Biochem, 2006, 75:189-210.
  32. 32. Zalckvar E, Berissi H, Mizrachy L, et al. DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy [J].EMBO Rep, 2009, 10(3): 285-292.
  33. 33. Gozuacik D, Bialik S, Raveh T, et al. DAP-kinase is a mediator of endoplasmic reticulum stress-induced caspase activation and autophagic cell death [J]. Cell Death Differ, 2008, 15(12):1875-1886.
  34. 34. Sakaki K, Wu J, Kaufman RJ. Protein kinase Ctheta is required for autophagy in response to stress in the endoplasmic reticulum [J]. J Biol Chem, 2008, 283(22): 15370-15380.
  35. 35. Vicencio JM, Ortiz C, Criollo A, et al. The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1 [J]. Cell Death Differ, 2009, 16(7): 1006-1017.
  36. 36. Vicencio JM, Lavandero S, Szabadkai G. Ca2 +, autophagy and protein degradation: thrown off balance in neurodegenerative disease [J]. Cell Calcium, 2010, 47(2): 112-121.
  37. 37. Wojcikiewicz RJ, Pearce MM, Sliter DA, et al. When worlds collide: IP(3) receptors and the ERAD pathway [J]. Cell Calcium,2009, 46(3): 147-153.