Activated α2-macroglobulin binding to human prostate cancer cells triggers insulin-like responses

Journal of Biological Chemistry

Volumn 290, Issue 15, 2015, Pages 9571-9587

  Misra, Uma Kant ^a   Pizzo, Salvatore Vincent ^a  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBODIES; CELL DEATH; CELL MEMBRANES; CELL PROLIFERATION; CHOLESTEROL; CYTOLOGY; DISEASES; FATTY ACIDS; GLUCOSE; INSULIN; PROTEINS; UROLOGY;

ACETYL-COA CARBOXYLASE; ALPHA-2-MACROGLOBULIN; CARBOXYL-TERMINAL DOMAIN; FATTY ACID SYNTHASE; HUMAN PROSTATE CANCER CELLS; PROSTATE CANCER CELLS; PROTEOLYTIC CLEAVAGE; STEROL REGULATORY ELEMENT-BINDING PROTEINS;

CELLS;

ACETYL COENZYME A CARBOXYLASE; ADENOSINE TRIPHOSPHATE CITRATE SYNTHASE; ALPHA 2 MACROGLOBULIN; CELL SURFACE PROTEIN; CHOLESTEROL; CHOLESTEROL ESTER; FATOSTATIN A; FATTY ACID; FATTY ACID SYNTHASE; FATTY ACID SYNTHASE INHIBITOR; GLUCOSE REGULATED PROTEIN 78; GLUCOSE TRANSPORTER 1; INSULIN; LACTIC ACID; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MESSENGER RNA; PHOSPHATIDYLCHOLINE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN ANTIBODY; PROTEIN INHIBITOR; STEROL REGULATORY ELEMENT BINDING PROTEIN 1C; STEROL REGULATORY ELEMENT BINDING PROTEIN 2; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; ANTIDIABETIC AGENT; CANCER ANTIBODY; FASN PROTEIN, HUMAN; GLUCOSE; HEAT SHOCK PROTEIN; LACTIC ACID DERIVATIVE; MOLECULAR CHAPERONE GRP78; PROTEIN BINDING; STEROL REGULATORY ELEMENT BINDING PROTEIN 1;

APOPTOSIS; ARTICLE; CARBOXY TERMINAL SEQUENCE; CELL PROLIFERATION; CELLULAR SECRETION; CONTROLLED STUDY; DRUG EFFECT; GLUCOSE TRANSPORT; HUMAN; HUMAN CELL; INSULIN LIKE ACTIVITY; LIPID METABOLISM; LIPOGENESIS; PRIORITY JOURNAL; PROSTATE CANCER; PROSTATE CANCER CELL LINE; PROTEIN BINDING; PROTEIN CLEAVAGE; PROTEIN EXPRESSION; RNA INTERFERENCE; UPREGULATION; DRUG EFFECTS; GENE EXPRESSION; GENETICS; IMMUNOLOGY; MALE; METABOLISM; PATHOLOGY; PROSTATE TUMOR; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; TUMOR CELL LINE; WESTERN BLOTTING;

ALPHA-MACROGLOBULINS; ANTIBODIES, NEOPLASM; BLOTTING, WESTERN; CELL LINE, TUMOR; CELL PROLIFERATION; CHOLESTEROL; FATTY ACID SYNTHASE, TYPE I; GENE EXPRESSION; GLUCOSE; HEAT-SHOCK PROTEINS; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN; LACTATES; LIPID METABOLISM; LIPOGENESIS; MALE; PROSTATIC NEOPLASMS; PROTEIN BINDING; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; STEROL REGULATORY ELEMENT BINDING PROTEIN 1;

EID: 84927127418     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M114.617837     Document Type: Article

References (98)

1. Jemal, A., Thomas, A., Murray, T., and Thun, M. (2002) Cancer statistics. CA Cancer J. Clin. 52, 23-47
2. Abate-Shen, C., and Shen, M. M. (2000) Molecular genetics of prostate cancer. Genes Dev. 14, 2410-2434
3. Montano, X., and Djamgoz, M. B. (2004) Epidermal growth factor, neurotrophins and the metastatic cascade in prostate cancer. FEBS Lett. 571, 1-8
4. Schlessinger, J. (2000) Cell signaling by receptor tyrosine kinases. Cell 103, 211-225
5. Manning, B. D., Cantley, L. C. (2007) AKT/PKB signaling: navigating downstream. Cell 129, 1261-1274
6. Misra, U. K., and Pizzo, S. V. (2012) Upregulation of mTORC2 activation by the selective agonist of EPAC, 8-CPT-2Me-cAMP, in prostate cancer cells: assembly of a multiprotein signaling complex. J. Cell Biochem. 113, 1488-1500
7. Misra, U. K., and Pizzo, S. V. (2005) Coordinate regulation of forskolininduced cellular proliferation in macrophages by protein kinase A/cAMPresponse element-binding protein (CREB) and Epac1-Rap1 signaling: effects of silencing CREB gene expression on Akt activation. J. Biol. Chem. 280, 38276-38289
8. Misra, U. K., and Pizzo, S. V. (2014) Activated α2-macroglobulin binding to cell surface GRP78 induces T-loop phosphorylation of Akt1 by PDK1 in association with Raptor. PLoS One 9, e88373
9. Misra, U. K., and Pizzo, S. V. (2009) Epac1-induced cellular proliferation in prostate cancer cells is mediated by B-Raf/ERK and mTOR signaling cas-cades. J. Cell Biochem. 108, 998-1011
10. Bayascas, J. R. (2010) PDK1: the major transducer of PI 3-kinase actions. Curr. Top. Microbiol. Immunol. 346, 9-29
11. Pearce, L. R., Komander, D., and Alessi, D. R. (2010) The nuts and bolts of AGC protein kinases. Nat. Rev. Mol. Cell Biol. 11, 9-22
12. Misra, U. K., and Pizzo, S. V. (2013) Raptor association with PDK1 is necessary for T-loop phosphorylation of Akt in prostate cancer cells stimulated with 8-CPT-2-Me-cAMP. J. Biochem. Pharmacol. Res. 1, 219-227
13. Hart, J. P., and Pizzo, S. V. (2006) in Principles and Clinical Practice (Coleman, R. W., Clowes, A. W., Goldhaber, S. Z., Marder, B. J., and George, J. N., eds) 5th Ed., pp. 395-407, Lippincott, Williams and Wilkins, Baltimore
14. Feldman, S. R., and Pizzo, S. V. (1984) Comparison of the binding of chicken α2-macroglobulin and ovomacroglobulin to the mammalian α2-macroglobulin receptor. Arch. Biochem. Biophys. 235, 267-275
15. Feldman, S. R., and Pizzo, S. V. (1986) Purification and characterization of a "half-molecule" α2-macroglobulin from the southern grass frog: absence of binding to the mammalian α2-macroglobulin receptor. Biochemistry 25, 721-727
16. Enghild, J. J., Thøgersen, I. B., Salvesen, G., Fey, G. H., Figler, N. L., Gonias, S. L., and Pizzo, S. V. (1990) α2-Macroglobulin from Limulus polyphemus exhibits proteinase inhibitory activity and participates in a hemolytic system. Biochemistry 29, 10070-10080
17. Thøgersen, I. B., Salvesen, G., Brucato, F. H., Pizzo, S. V., and Enghild, J. J. (1992) Purification and characterization of an α2-macroglobulin proteinase inhibitor from the mollusc Octopus vulgaris. Biochem. J. 285, 521-527
18. Misra, U. K., Payne, S., and Pizzo, S. V. (2011) Ligation of prostate cancer cell surface GRP78 activates a proproliferative and antiapoptotic feedback loop: a role for secreted prostate-specific antigen. J. Biol. Chem. 286, 1248-1259
19. Feldman, S. R., Gonias, S. L., and Pizzo, S. V. (1985) Model of α2-macroglobulin structure and function. Proc. Natl. Acad. Sci. U.S.A. 82, 5700-5704
20. Misra, U. K., Chu, C. T., Rubenstein, D. S., Gawdi, G., and Pizzo, S. V. (1993) Receptor-recognized α2-macroglobulin-methylamine elevates intracellular calcium, inositol phosphates and cyclic AMP in murine peritoneal macrophages. Biochem. J. 290, 885-891
21. Misra, U. K., Chu, C. T., Gawdi, G., and Pizzo, S. V. (1994) Evidence for a second α2-macroglobulin receptor. J. Biol. Chem. 269, 12541-12547
22. Misra, U. K., Gonzalez-Gronow, M., Gawdi, G., Hart, J. P., Johnson, C. E., and Pizzo, S. V. (2002) The role of Grp 78 in α2-macroglobulin-induced signal transduction. Evidence from RNA interference that the low density lipoprotein receptor-related protein is associated with, but not necessary for, GRP 78-mediated signal transduction. J. Biol. Chem. 277, 42082-42087
23. Misra, U. K., Gonzalez-Gronow, M., Gawdi, G., Wang, F., and Pizzo, S. V. (2004) A novel receptor function for the heat shock protein Grp78: silencing of Grp78 gene expression attenuates α2M-induced signalling. Cell. Signal. 16, 929-938
24. Ma, Y., and Hendershot, L. M. (2004) The role of the unfolded protein response in tumour development: friend or foe? Nat. Rev. Cancer 4, 966-977
25. Misra, U. K., Deedwania, R., and Pizzo, S. V. (2006) Activation and crosstalk between Akt, NF-B, and unfolded protein response signaling in 1-LN prostate cancer cells consequent to ligation of cell surface-associated GRP78. J. Biol. Chem. 281, 13694-13707
26. Gonzalez-Gronow, M., Pizzo, S. V., and Misra, U. K. (2013) Cellular Trafficking of Cell Stress Proteins in Health and Diseases (Henderson, B., and Pockley, A. G., eds), pp. 229-242, Springer Science Business Media, Dordrecht, The Netherlands
27. Misra, U. K., Gawdi, G., Gonzalez-Gronow, M., and Pizzo, S. V. (1999) Coordinate regulation of the α2-macroglobulin signaling receptor and the low density lipoprotein receptor-related protein/α2-macroglobulin receptor by insulin. J. Biol. Chem. 274, 25785-25791
28. Asplin, I. R., Misra, U. K., Gawdi, G., Gonzalez-Gronow, M., and Pizzo, S. V. (2000) Selective upregulated expression of the α2-macroglobulin signaling receptor in highly metastatic 1-LN prostate carcinoma cells. Arch. Biochem. Biophys. 383, 135-141
29. Misra, U. K., Deedwania, R., and Pizzo, S. V. (2005) Binding of activated α2-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK. J. Biol. Chem. 280, 26278-26286
30. Misra, U. K., and Pizzo, S. V. (1998) Binding of receptor-recognized forms of α2-macroglobulin to the α2-macroglobulin signaling receptor activates phosphatidylinositol 3-kinase. J. Biol. Chem. 273, 13399-13402
31. Misra, U. K., Akabani, G., and Pizzo, S. V. (2002) The role of cAMP-dependent signaling in receptor-recognized forms of α2-macroglobulin-induced cellular proliferation. J. Biol. Chem. 277, 36509-36520
32. Misra, U. K., Gonzalez-Gronow, M., Gawdi, G., and Pizzo, S. V. (1997) Up-regulation of the α2-macroglobulin signaling receptor in rheumatoid synovial fibroblasts. J. Biol. Chem. 272, 497-502
33. Misra, U. K., and Pizzo, S. V. (1998) Ligation of the α2M signalling receptor elevates the levels of p21Ras-GTP in macrophages. Cell. Signal. 10, 441-445
34. Misra, U. K., and Pizzo, S. V. (1998) Ligation of the α2Msignaling receptor with receptor-recognized forms of α2-macroglobulin initiates protein and DNA synthesis in macrophages. The effect of intracellular calcium. Biochim. Biophys. Acta 1401, 121-128
35. Misra, U. K., and Pizzo, S. V. (2004) Potentiation of signal transduction mitogenesis and cellular proliferation upon binding of receptor-recognized forms of α2-macroglobulin to 1-LN prostate cancer cells. Cell. Signal. 16, 487-496
36. Misra, U. K., and Pizzo, S. V. (2012) Receptor-recognized α2-macroglobulin binds to cell surface-associated GRP78 and activates mTORC1 and mTORC2 signaling in prostate cancer cells. PLoS One 7, e51735
37. Misra, U. K., and Pizzo, S. V. (2007) Upregulation of AKT1 protein expression in forskolin-stimulated macrophage: evidence from ChIP analysis that CREB binds to and activates the AKT1 promoter. J. Cell. Biochem. 100, 1022-1033
38. Misra, U. K., and Pizzo, S. V. (2010) Ligation of cell surface GRP78 with antibody directed against the COOH-terminal domain of GRP78 suppresses Ras/MAPK and PI 3-kinase/AKT signaling while promoting caspase activation in human prostate cancer cells. Cancer Biol. Ther. 9, 2 142-152
39. Misra, U. K., Mowery, Y., Kaczowka, S., and Pizzo, S. V. (2009) Ligation of cancer cell surface GRP78 with antibodies directed against its COOHterminal domain up-regulates p53 activity and promotes apoptosis. Mol. Cancer Ther. 8, 1350-1362
40. Gonzalez-Gronow, M., Cuchacovich, M., Llanos, C., Urzua, C., Gawdi, G., and Pizzo, S. V. (2006) Prostate cancer cell proliferation in vitro is modulated by antibodies against glucose-regulated protein 78 isolated from patient serum. Cancer Res. 66, 11424-11431
41. Mintz, P. J., Kim, J., Do, K. A., Wang, X., Zinner, R. G., Cristofanilli, M., Arap, M. A., Hong, W. K., Troncoso, P., Logothetis, C. J., Pasqualini, R., and Arap, W. (2003) Fingerprinting the circulating repertoire of antibodies from cancer patients. Nat. Biotechnol. 21, 57-63
42. Arap, M. A., Lahdenranta, J., Mintz, P. J., Hajitou, A., Sarkis, A. S., Arap, W., and Pasqualini, R. (2004) Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands. Cancer Cell 6, 275-284
43. de Ridder, G. G., Gonzalez-Gronow, M., Ray, R., and Pizzo, S. V. (2011) Autoantibodies against cell surface GRP78 promote tumor growth in a murine model of melanoma. Melanoma Res. 21, 35-43
44. de Ridder, G. G., Ray, R., and Pizzo, S. V. (2012) A murine monoclonal antibody directed against the carboxyl-terminal domain of GRP78 suppresses melanoma growth in mice. Melanoma Res. 22, 225-235
45. Kanoh, Y., Ohtani, N., Mashiko, T., Ohtani, S., Nishikawa, T., Egawa, S., Baba, S., and Ohtani, H. (2001) Levels of α2macroglobulin can predict bone metastases in prostate cancer. Anticancer Res. 21, 551-556
46. DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G., and Thompson, C. B. (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7, 11-20
47. Cantor, J. R., and Sabatini, D. M. (2012) Cancer cell metabolism: one hallmark, many faces. Cancer Discov. 2, 882-898
48. Menendez, J. A., and Lupu, R. (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 7, 763-777
49. Ros, S., Santos, C. R., Moco, S., Baenke, F., Kelly, G., Howell, M., Zamboni, N., and Schulze, (2012) Functional metabolic screen identifies 6-phospho-fructo-2-kinase/fructose-2,6-biphosphatase 4 as an important regulator of prostate cancer cell survival. Cancer Discov. 2, 328-343
50. Flavin, R., Zadra, G., and Loda, M. (2011) Metabolic alterations and targeted therapies in prostate cancer. J. Pathol. 223, 283-294
51. Baenke, F., Peck, B., Miess, H., and Schulze, A. (2013) Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development. Dis. Model Mech. 6, 1353-1363
52. Lunt, S. Y., and Vander Heiden, M. G. (2011) Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 27, 441-464
53. Gatenby, R. A., and Gillies, R. J. (2004) Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer 4, 891-899
54. Vander Heiden, M. G. (2011) Targeting cancer metabolism: a therapeutic window opens. Nat. Rev. Drug Discov. 10, 671-684
55. Warburg, O. (1956) On the origin of cancer cells. Science 123, 309-314
56. Medes, G., Thomas, A., and Weinhouse, S. (1953) Metabolism of neoplastic tissue. IV. A study of lipid synthesis in neoplastic tissue slices in vitro. Cancer Res. 13, 27-29
57. Rossi, S., Graner, E., Febbo, P., Weinstein, L., Bhattacharya, N., Onody, T., Bubley, G., Balk, S., and Loda, M. (2003) Fatty acid synthase expression defines distinct molecular signatures in prostate cancer. Mol. Cancer Res. 1, 707-715
58. Van de Sande, T., Roskams, T., Lerut, E., Joniau, S., Van Poppel, H., Verhoeven, G., and Swinnen, J. V. (2005) High-level expression of fatty-acid synthase in human prostate cancer tissues is linked to activation and nuclear localization of Akt/PKB. J. Pathol. 206, 214-219
59. Santos, C. R., and Schulze, A. (2012) Lipid metabolism in cancer. FEBS J. 279, 2610-2623
60. Yoshii, Y., Furukawa, T., Oyama, N., Hasegawa, Y., Kiyono, Y., Nishii, R., Waki, A., Tsuji, A. B., Sogawa, C., Wakizaka, H., Fukumura, T., Yoshii, H., Fujibayashi, Y., Lewis, J. S., and Saga, T. (2013) Fatty acid synthase is a key target in multiple essential tumor functions of prostate cancer: uptake of radiolabeled acetate as a predictor of the targeted therapy outcome. PloS One 8, e64570
61. Van de Sande, T., De Schrijver, E., Heyns, W., Verhoeven, G., and Swinnen, J. V. (2002) Role of the phosphatidylinositol 3″-kinase/PTEN/Akt kinase pathway in the overexpression of fatty-acid synthase in LNCaP prostate cancer cells. Cancer Res. 62, 642-646
62. Hatzivassiliou, G., Zhao, F., Bauer, D. E., Andreadis, C., Shaw, A. N., Dhanak, D., Hingorani, S. R., Tuveson, D. A., and Thompson, C. B. (2005) ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311-321
63. Griffiths, B., Lewis, C. A., Bensaad, K., Ros, S., Zhang, Q., Ferber, E. C., Konisti, S., Peck, B., Miess, H., East, P., Wakelam, M., Harris, A. L., and Schulze, A. (2013) Sterol regulatory element binding protein-dependent regulation of lipid synthesis supports cell survival and tumor growth. Cancer Metab. 1, 3
64. Porstmann, T., Griffiths, B., Chung, V.-L., Delpuech, O., Griffiths, J. R., Downward, J., and Schulze, A. (2005) PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene 24, 6465-6481
65. Liu, Y. (2006) Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer. Prostate Cancer Prostatic Dis. 9, 230-234
66. Horton, J. D., Goldstein, J. L., and Brown, M. S. (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125-1131
67. Goldstein, J. L., DeBose-Boyd, R. A., and Brown, M. S. (2006) Protein sensors for membrane sterols. Cell 124, 35-46
68. Shao, W., and Espenshade, P. J. (2012) Expanding roles for SREBP in metabolism. Cell Metab. 16, 414-419
69. Yellaturu, C. R., Deng, X., Park, E. A., Raghow, R., and Elam, M. B. (2009) Insulin enhances the biogenesis of nuclear sterol regulatory element-binding protein (SREBP)-1c by posttranscriptional down-regulation of In-sig-2A and its dissociation from SREBP cleavage-activating protein (SCAP).SREBP-1c complex. J. Biol. Chem. 284, 31726-31734
70. Owen, J. L., Zhang, Y., Bae, S.-H., Farooqi, M. S., Liang, G., Hammer, R. E., Goldstein, J. L., and Brown, M. S. (2012) Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Proc. Natl. Acad. Sci. U.S.A. 109, 16184-16189
71. Bauer, D. E., Hatzivassiliou, G., Zhao, F., Andreadis, C., and Thompson, C. B. (2005) ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24, 6314-6322
72. Beckers, A., Organe, S., Timmermans, L., Scheys, K., Peeters, A., Brusselmans, K., Verhoeven, G., and Swinnen, J. V. (2007) Chemical inhibition of acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells. Cancer Res. 67, 8180-8187
73. Pelton, K., Freeman, M. R., and Solomon, K. R. (2012) Cholesterol and prostate cancer. Curr. Opin. Pharmacol. 12, 751-759
74. Krycer, J. R., and Brown, A. J. (2013) Cholesterol accumulation in prostate cancer: a classic observation from a modern perspective. Biochim. Biophys. Acta 1835, 219-229
75. Lingwood, D., and Simons, K. (2010) Lipid rafts as a membrane-organizing principle. Science 327, 46-50
76. Yue, S., Li, J., Lee, S.-Y., Lee, H.-J., Shao, T., Song, B., Cheng, L., Masterson, T. A., Liu, X., Ratliff, T. L., and Cheng, J.-X. (2014) Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab. 19, 393-406
77. Brown, M. S., and Goldstein, J. L. (1997) The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89, 331-340
78. Porstmann, T., Santos, C. R., Griffiths, B., Cully, M., Wu, M., Leevers, S., Griffiths, J. R., Chung, Y.-L., and Schulze, A. (2008) SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8, 224-236
79. Peterson, T. R., Sengupta, S. S., Harris, T. E., Carmack, A. E., Kang, S. A., Balderas, E., Guertin, D. A., Madden, K. L., Carpenter, A. E., Finck, B. N., and Sabatini, D. M. (2011) mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146, 408-420
80. Ridgway, N. D. (2013) The role of phosphatidylcholine and choline metabolites to cell proliferation and survival. Crit. Rev. Biochem. Mol. Biol. 48, 20-38
81. Glunde, K., Bhujwalla, Z. M., and Ronen, S. M. (2011) Choline metabolism in malignant transformation. Nat. Rev. Cancer 11, 835-848
82. Misra, U. K., and Pizzo, S. V. (2002) Regulation of cytosolic phospholipase A2 activity in macrophages stimulated with receptor-recognized forms of alpha 2-macroglobulin: role in mitogenesis and cell proliferation. J. Biol. Chem. 277, 4069-4078
83. Misra, U. K., and Pizzo, S. V. (1999) Upregulation of macrophage plasma membrane and nuclear phospholipaseDactivity on ligation of the alpha2-macroglobulin signaling receptor: involvement of heterotrimeric and monomeric G proteins. Arch. Biochem. Biophys. 363, 68-80
84. Misra, U. K., and Pizzo, S. V. (2001) Induction of cyclooxygenase-2 synthesis by ligation of the macrophage alpha(2)-macroglobulin signalling receptor. Cell. Signal. 13, 801-808
85. Bradford, M. M. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248-254
86. Bligh, E. G., and Dyer, W. J. (1959) A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37, 911-917
87. Kennedy, E. P., and Weiss, S. B. (1956) The function of cytidine coenzymes in the biosynthesis of phospholipids. J. Biol. Chem. 222, 193-214
88. Vander Heiden, M. G., Cantley, L. C., and Thompson, C. B. (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029-1033
89. Kato, Y., Ozawa, S., Miyamoto, C., Maehata, Y., Suzuki, A., Maeda, T., and Baba, Y. (2013) Acidic extracellular microenvironment and cancer. Cancer Cell Int. 13, 89-96
90. Walenta, S., Salameh, A., Lyng, H., Evensen, J. F., Mitze, M., Rofstad, E. K., Mueller-Klieser, W. (1997) Correlation of high lactate levels in head and neck tumors with incidence of metastasis. Am. J. Pathol. 150, 409-415
91. Kamisuki, S., Mao, Q., Abu-Elheiga, L., Gu, Z., Kugimiya, A., Kwon, Y., Shinohara, T., Kawazoe, Y., Sato, S., Asakura, K., Choo, H. Y., Sakai, J., Wakil, S. J., and Uesugi, M. (2009) A small molecule that blocks fat syn-thesis by inhibiting the activation of SREBP. Chem. Biol. 16, 882-892
92. Li, X., Chen, Y. T., Hu, P., and Huang, W. C. (2014) Fatostatin displays high anti-tumor activity in prostate cancer by blocking SREBP-regulated metabolic pathways and androgen receptor signaling. Mol. Cancer Ther. 13, 855-866
93. van der Sanden, M. H., Houweling, M., van Golde, L. M., and Vaandrager, A. B. (2003) Inhibition of phosphatidylcholine synthesis induces expression of the endoplasmic reticulum stress and apoptosisrelated protein CCAAT/enhancer-binding protein-homologous protein (CHOP/GADD153). Biochem. J. 369, 643-650
94. Lagace, T. A., Storey, M. K., and Ridgway, N. D. (2000) Regulation of phosphatidylcholine metabolism in Chinese hamster ovary cells by the sterol regulatory element-binding protein (SREBP)/SREBP cleavage-activating protein pathway. J. Biol. Chem. 275, 14367-14374
95. Bhattacharjee, G., Misra, U. K., Gawdi, G., Cianciolo, G., and Pizzo, S. V. (2001) Inducible expression of the alpha2-macroglobulin signaling receptor in response to antigenic stimulation: a study of second messenger generation. J. Cell. Biochem. 82, 260-270
96. Misra, U. K., Payne, S., and Pizzo, S. V. (2013) The monomeric receptor binding domain of tetrameric α2-macroglobulin binds to cell surface GRP78 triggering equivalent activation of signaling cascades. Biochemistry 52, 4014-4025
97. Steiner, D. F., Chan, S. J., Welsh, J. M., and Kwok, S. C. (1985) Structure and evolution of the insulin gene. Annu. Rev. Genet. 19, 463-484
98. Adamson, E. D. (1987) Oncogenes in development. Development 99, 449-471