Cellular responses to individual amino-acid depletion in antibody-expressing and parental CHO cell lines

Biotechnology and Bioengineering

Volumn 111, Issue 5, 2014, Pages 965-979

  Fomina Yadlin, Dina ^a   Gosink, John J ^b   McCoy, Rebecca ^a   Follstad, Brian ^a   Morris, Arvia ^a   Russell, Chris B ^b   McGrew, Jeffrey T ^a  

^a AMGEN INC   (United States)

^b Molecular Sciences and Computational Biology   (United States)

Author keywords

Amino acid depletion; Cell cycle arrest; Cellular signaling; Chinese hamster ovary; Cholesterol biosynthesis; Gene expression; Lipid metabolism; Microarray; Nonessential amino acids; Pathway analysis; Production conditions

Indexed keywords

ANTIBIOTICS; ANTIBODIES; BIOCHEMISTRY; BIOSYNTHESIS; CELL CULTURE; CELLS; GENE EXPRESSION; METABOLISM; MICROARRAYS; PHYSIOLOGY; PRODUCTION ENGINEERING;

AMINO-ACID DEPLETION; CELL-CYCLE ARREST; CELLULAR SIGNALING; CHINESE HAMSTER OVARY; LIPID METABOLISMS; PATHWAY ANALYSIS;

AMINO ACIDS;

ASPARAGINE; DNA; GLUTAMINE; LEUCINE; MAMMALIAN TARGET OF RAPAMYCIN; RECOMBINANT ANTIBODY; STEROL REGULATORY ELEMENT BINDING PROTEIN 1; STEROL REGULATORY ELEMENT BINDING PROTEIN 2; TRANSCRIPTION FACTOR E2F;

AMINO ACID DEPLETION; AMINO ACID RESPONSE PATHWAY; AMINO ACID WITHDRAWAL; ANIMAL CELL; ANTIBODY EXPRESSING CHO CELL LINE; ARTICLE; CELL CULTURE; CELL CYCLE ARREST; CELL CYCLE G0 PHASE; CELL CYCLE G1 PHASE; CELL CYCLE PROGRESSION; CELL FUNCTION; CELL GROWTH; CELLULAR RESPONSE; CHO CELL; CHO K1 CELL LINE; CONTROLLED STUDY; CS9 CELL LINE; DNA REPLICATION; DOWN REGULATION; FED BATCH CULTURE; FEMALE; GROWTH INHIBITION; HOMEOSTASIS; LIPID HOMEOSTASIS; LIPID METABOLISM; NONHUMAN; NUCLEOTIDE METABOLISM; PARENTAL CHO CELL LINE; PROTEIN DEPLETION; PROTEIN FUNCTION; PROTEIN SYNTHESIS; SIGNAL TRANSDUCTION;

CRICETULUS GRISEUS; MAMMALIA;

AMINO-ACID DEPLETION; CELL CYCLE ARREST; CELLULAR SIGNALING; CHINESE HAMSTER OVARY; CHOLESTEROL BIOSYNTHESIS; GENE EXPRESSION; LIPID METABOLISM; MICROARRAY; NONESSENTIAL AMINO ACIDS; PATHWAY ANALYSIS; PRODUCTION CONDITIONS;

AMINO ACIDS; ANIMALS; ANTIBODIES; CELL CULTURE TECHNIQUES; CELL PHYSIOLOGICAL PROCESSES; CHO CELLS; CRICETINAE; CRICETULUS; CULTURE MEDIA; LIPID METABOLISM; RECOMBINANT PROTEINS;

EID: 84897074858     PISSN: 00063592     EISSN: 10970290     Source Type: Journal    
DOI: 10.1002/bit.25155     Document Type: Article

References (62)

1. Aldrich TL, Viaje A, Morris AE. 2003. EASE vectors for rapid stable expression of recombinant antibodies. Biotechnol Prog 19(5):1433-1438.
2. Ameri K, Harris AL. 2008. Activating transcription factor 4. Int J Biochem Cell Biol 40(1):14-21.
3. Andrulis IL, Chen J, Ray PN. 1987. Isolation of human cDNAs for asparagine synthetase and expression in Jensen rat sarcoma cells. Mol Cell Biol 7(7):2435-2443.
4. Averous J, Bruhat A, Jousse C, Carraro V, Thiel G, Fafournoux P. 2004. Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation. J Biol Chem 279(7):5288-5297.
5. Baird TD, Wek RC. 2012. Eukaryotic initiation factor 2 phosphorylation and translational control in metabolism. Adv Nutr 3(3):307-321.
6. Bhatia B, Hsieh M, Kenney AM, Nahle Z. 2011. Mitogenic Sonic hedgehog signaling drives E2F1-dependent lipogenesis in progenitor cells and medulloblastoma. Oncogene 30(4):410-422.
7. Canepa ET, Scassa ME, Ceruti JM, Marazita MC, Carcagno AL, Sirkin PF, Ogara MF. 2007. INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions. IUBMB Life 59(7):419-426.
8. Chee Furng Wong D, Tin Kam Wong K, Tang Goh L, Kiat Heng C, Gek Sim Yap M. 2005. Impact of dynamic online fed-batch strategies on metabolism, productivity and N-glycosylation quality in CHO cell cultures. Biotechnol Bioeng 89(2):164-177.
9. Clarke C, Henry M, Doolan P, Kelly S, Aherne S, Sanchez N, Kelly P, Kinsella P, Breen L, Madden SF, Zhang L, Leonard M, Clynes M, Meleady P, Barron N. 2012. Integrated miRNA, mRNA and protein expression analysis reveals the role of post-transcriptional regulation in controlling CHO cell growth rate. BMC Genomics 13:656.
10. De Jesus M, Wurm FM. 2011. Manufacturing recombinant proteins in kg-ton quantities using animal cells in bioreactors. Eur J Pharm Biopharm 78(2):184-188.
11. Deval C, Chaveroux C, Maurin AC, Cherasse Y, Parry L, Carraro V, Milenkovic D, Ferrara M, Bruhat A, Jousse C, et al. 2009. Amino acid limitation regulates the expression of genes involved in several specific biological processes through GCN2-dependent and GCN2-independent pathways. FEBS J 276(3):707-718.
12. Dorai H, Kyung YS, Ellis D, Kinney C, Lin C, Jan D, Moore G, Betenbaugh MJ. 2009. Expression of anti-apoptosis genes alters lactate metabolism of Chinese Hamster Ovary cells in culture. Biotechnol Bioeng 103(3):592-608.
13. Du Z, Treiber D, McCoy RE, Miller AK, Han M, He F, Domnitz S, Heath C, Reddy P. 2013. Non-invasive UPR monitoring system and its applications in CHO production cultures. Biotechnol Bioeng 110(8):2184-2194.
14. Ellison BS, Zanin MK, Boackle RJ. 2007. Complement susceptibility in glutamine deprived breast cancer cells. Cell Div 2:20.
15. Follstad B, McCoy R, Morris A. 2013. Mammalian cell culture. WO Patent 2, 013, 006, 479.
16. Frank CL, Ge X, Xie Z, Zhou Y, Tsai LH. 2010. Control of activating transcription factor 4 (ATF4) persistence by multisite phosphorylation impacts cell cycle progression and neurogenesis. J Biol Chem 285(43):33324-33337.
17. Fussenegger M, Schlatter S, Datwyler D, Mazur X, Bailey JE. 1998. Controlled proliferation by multigene metabolic engineering enhances the productivity of Chinese hamster ovary cells. Nat Biotechnol 16(5):468-472.
18. Gawlitzek M, Petraglia CT, Luo S. 2012. Production of proteins in glutamine-free cell culture media. EP Patent 2, 464, 725.
19. Gong SS, Guerrini L, Basilico C. 1991. Regulation of asparagine synthetase gene expression by amino acid starvation. Mol Cell Biol 11(12):6059-6066.
20. Gorin A, Gabitova L, Astsaturov I. 2012. Regulation of cholesterol biosynthesis and cancer signaling. Curr Opin Pharmacol 12(6):710-715.
21. Guo F, Cavener DR. 2007. The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metab 5(2):103-114.
22. Guo D, Gao A, Michels DA, Feeney L, Eng M, Chan B, Laird MW, Zhang B, Yu XC, Joly J, et al. 2010. Mechanisms of unintended amino acid sequence changes in recombinant monoclonal antibodies expressed in Chinese Hamster Ovary (CHO) cells. Biotechnol Bioeng 107(1):163-171.
23. Hara K, Yonezawa K, Weng QP, Kozlowski MT, Belham C, Avruch J. 1998. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem 273(23):14484-14494.
24. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D. 2000. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6(5):1099-1108.
25. Haredy AM, Nishizawa A, Honda K, Ohya T, Ohtake H, Omasa T. 2013. Improved antibody production in Chinese hamster ovary cells by ATF4 overexpression. Cytotechnology. doi: 10.1007/s10616-013-9631-x (in press).
26. Hong JK, Cho SM, Yoon SK. 2010. Substitution of glutamine by glutamate enhances production and galactosylation of recombinant IgG in Chinese hamster ovary cells. Appl Microbiol Biotechnol 88(4):869-876.
27. Huang YM, Hu W, Rustandi E, Chang K, Yusuf-Makagiansar H, Ryll T. 2010. Maximizing productivity of CHO cell-based fed-batch culture using chemically defined media conditions and typical manufacturing equipment. Biotechnol Prog 26(5):1400-1410.
28. Jardon MA, Sattha B, Braasch K, Leung AO, Cote HC, Butler M, Gorski SM, Piret JM. 2012. Inhibition of glutamine-dependent autophagy increases t-PA production in CHO cell fed-batch processes. Biotechnol Bioeng 109(5):1228-1238.
29. Jeon TI, Osborne TF. 2012. SREBPs: Metabolic integrators in physiology and metabolism. Trends Endocrinol Metab 23(2):65-72.
30. Jousse C, Deval C, Maurin AC, Parry L, Cherasse Y, Chaveroux C, Lefloch R, Lenormand P, Bruhat A, Fafournoux P. 2007. TRB3 inhibits the transcriptional activation of stress-regulated genes by a negative feedback on the ATF4 pathway. J Biol Chem 282(21):15851-15861.
31. Kantardjieff A, Jacob NM, Yee JC, Epstein E, Kok YJ, Philp R, Betenbaugh M, Hu WS. 2010. Transcriptome and proteome analysis of Chinese hamster ovary cells under low temperature and butyrate treatment. J Biotechnol 145(2):143-159.
32. Kao FT, Puck TT. 1967. Genetics of somatic mammalian cells. IV. Properties of Chinese hamster cell mutants with respect to the requirement for proline. Genetics 55(3):513-524.
33. Khattak SF, Xing Z, Kenty B, Koyrakh I, Li ZJ. 2010. Feed development for fed-batch CHO production process by semisteady state analysis. Biotechnol Prog 26(3):797-804.
34. Khetan A, Huang YM, Dolnikova J, Pederson NE, Wen D, Yusuf-Makagiansar H, Chen P, Ryll T. 2010. Control of misincorporation of serine for asparagine during antibody production using CHO cells. Biotechnol Bioeng 107(1):116-123.
35. Kilberg MS, Pan YX, Chen H, Leung-Pineda V. 2005. Nutritional control of gene expression: How mammalian cells respond to amino acid limitation. Annu Rev Nutr 25:59-85.
36. Kilberg MS, Shan J, Su N. 2009. ATF4-dependent transcription mediates signaling of amino acid limitation. Trends Endocrinol Metab 20(9):436-443.
37. Kim DY, Chaudhry MA, Kennard ML, Jardon MA, Braasch K, Dionne B, Butler M, Piret JM. 2012. Fed-batch CHO cell t-PA production and feed glutamine replacement to reduce ammonia production. Biotechnol Prog 29(1):165-175.
38. Kober L, Zehe C, Bode J. 2012. Development of a novel ER stress based selection system for the isolation of highly productive clones. Biotechnol Bioeng 109(10):2599-2611.
39. Krejci O, Starkova J, Otova B, Madzo J, Kalinova M, Hrusak O, Trka J. 2004. Upregulation of asparagine synthetase fails to avert cell cycle arrest induced by L-asparaginase in TEL/AML1-positive leukaemic cells. Leukemia 18(3):434-441.
40. Kurano N, Leist C, Messi F, Kurano S, Fiechter A. 1990. Growth behavior of Chinese hamster ovary cells in a compact loop bioreactor. 2. Effects of medium components and waste products. J Biotechnol 15(1):113-128.
41. Lee JI, Dominy JE, Jr., Sikalidis AK, Hirschberger LL, Wang W, Stipanuk MH. 2008. HepG2/C3A cells respond to cysteine deprivation by induction of the amino acid deprivation/integrated stress response pathway. Physiol Genomics 33(2):218-229.
42. Lu F, Toh PC, Burnett I, Li F, Hudson T, Amanullah A, Li J. 2013. Automated dynamic fed-batch process and media optimization for high productivity cell culture process development. Biotechnol Bioeng 110(1):191-205.
43. Mazur X, Fussenegger M, Renner WA, Bailey JE. 1998. Higher productivity of growth-arrested Chinese hamster ovary cells expressing the cyclin-dependent kinase inhibitor p27. Biotechnol Prog 14(5):705-713.
44. Murphy TC, Woods NR, Dickson AJ. 2001. Expression of the transcription factor GADD153 is an indicator of apoptosis for recombinant chinese hamster ovary (CHO) cells. Biotechnol Bioeng 75(6):621-629.
45. Ohya T, Hayashi T, Kiyama E, Nishii H, Miki H, Kobayashi K, Honda K, Omasa T, Ohtake H. 2008. Improved production of recombinant human antithrombin III in Chinese hamster ovary cells by ATF4 overexpression. Biotechnol Bioeng 100(2):317-324.
46. Palii SS, Kays CE, Deval C, Bruhat A, Fafournoux P, Kilberg MS. 2009. Specificity of amino acid regulated gene expression: Analysis of genes subjected to either complete or single amino acid deprivation. Amino Acids 37(1):79-88.
47. Pan YX, Chen H, Thiaville MM, Kilberg MS. 2007. Activation of the ATF3 gene through a co-ordinated amino acid-sensing response programme that controls transcriptional regulation of responsive genes following amino acid limitation. Biochem J 401(1):299-307.
48. Patterson MK, Jr., Maxwell MD. 1970. Effects of L-asparagine deprivation on the cell cycle of the Jensen sarcoma. Cancer Res 30(4):1064-1067.
49. Polager S, Ginsberg D. 2008. E2F-At the crossroads of life and death. Trends Cell Biol 18(11):528-535.
50. Rajendra Y, Kiseljak D, Baldi L, Hacker DL, Wurm FM. 2012. Reduced glutamine concentration improves protein production in growth-arrested CHO-DG44 and HEK-293E cells. Biotechnol Lett 34(4):619-626.
51. Rasmussen B, Davis R, Thomas J, Reddy P. 1998. Isolation, characterization and recombinant protein expression in Veggie-CHO: A serum-free CHO host cell line. Cytotechnology 28(1-3):31-42.
52. Seewoster T, Lehmann J. 1995. Influence of targeted asparagine starvation on extra- and intracellular amino acid pools of cultivated Chinese hamster ovary cells. Appl Microbiol Biotechnol 44(3-4):344-350.
53. Siu F, Chen C, Zhong C, Kilberg MS. 2001. CCAAT/enhancer-binding protein-beta is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. J Biol Chem 276(51):48100-48107.
54. Siu F, Bain PJ, LeBlanc-Chaffin R, Chen H, Kilberg MS. 2002. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. J Biol Chem 277(27):24120-24127.
55. Su N, Kilberg MS. 2008. C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene. J Biol Chem 283(50):35106-35117.
56. Underhill MF, Birch JR, Smales CM, Naylor LH. 2005. eIF2alpha phosphorylation, stress perception, and the shutdown of global protein synthesis in cultured CHO cells. Biotechnol Bioeng 89(7):805-814.
57. Wasa M, Bode BP, Abcouwer SF, Collins CL, Tanabe KK, Souba WW. 1996. Glutamine as a regulator of DNA and protein biosynthesis in human solid tumor cell lines. Ann Surg 224(2):189-197.
58. Weinberg F, Chandel NS. 2009. Mitochondrial metabolism and cancer. Ann N Y Acad Sci 1177:66-73.
59. Wen D, Vecchi MM, Gu S, Su L, Dolnikova J, Huang YM, Foley SF, Garber E, Pederson N, Meier W. 2009. Discovery and investigation of misincorporation of serine at asparagine positions in recombinant proteins expressed in Chinese hamster ovary cells. J Biol Chem 284(47):32686-32694.
60. Xie L, Wang DI. 1994. Stoichiometric analysis of animal cell growth and its application in medium design. Biotechnol Bioeng 43(11):1164-1174.
61. Xie L, Wang DI. 1996. Material balance studies on animal cell metabolism using a stoichiometrically based reaction network. Biotechnol Bioeng 52(5):579-590.
62. Zagari F, Jordan M, Stettler M, Broly H, Wurm FM. 2012. Lactate metabolism shift in CHO cell culture: The role of mitochondrial oxidative activity. N Biotechnol 30(2):238-245.