Abstract
The constitutive activation of nuclear factor κB (NFκB) helps a variety of tumors to resist apoptosis and desensitizes them to chemotherapy, but the causes are still largely unknown. We have analysed this phenomenon in eight mutant cell lines derived from human 293 cells, selected for NFκB-dependent expression of a marker gene, and also in seven tumor-derived cell lines. Conditioned media from all of these cells stimulated the activation of NFκB (up to 30-fold) in indicator cells carrying an NFκB-responsive reporter. Therefore, secretion of extracellular factors as the cause of constitutive activation seems to be general. The mRNAs encoding several different cytokines and growth factors were greatly overexpressed in the tumor and mutant cells. The pattern of overexpression was distinct in each cell line, indicating that the phenomenon is complex. Two secreted factors whose roles in the constitutive activation of NFκB are not well defined were investigated further as pure proteins: transforming growth factor β2 (TGFβ2) and fibroblast growth factor 5 (FGF5) were both highly expressed in some mutant clones and tumor cell lines, each activated NFκB alone, and the combination was synergistic. Our data indicate that a group of different factors, expressed at abnormally high levels, can contribute singly and synergistically to the constitutive activation of NFκB in all of the mutant and tumor cell lines we studied. Since several NFκB target genes encode secreted proteins that induce NFκB, autocrine loops are likely to be ubiquitously important in the constitutive activation of NFκB in cancer. We provide the first evidence of the general, complex, and synergistic activation of NFκB in tumor and mutant cell lines through the action of secreted factors and suggest that the same explanation is likely for the constitutive activation of NFκB in cancers.
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References
Alitalo K and Carmeliet P . (2002). Cancer Cell, 1, 219–227.
Arlt A, Vorndamm J, Muerkoster S, Yu H, Schmidt WE, Folsch UR and Schafer H . (2002). Cancer Res., 62, 910–916.
Baeuerle PA and Henkel T . (1994). Annu. Rev. Immunol., 12, 141–179.
Baldwin AS . (2001). J. Clin. Invest., 107, 241–246.
Bhat-Nakshatri P, Sweeney CJ and Nakshatri H . (2002). Oncogene, 21, 2066–2078.
Brach MA, Henschler R, Mertelsmann RH and Herrmann F . (1991). Pathobiology, 59, 284–288.
Brown JM, Corey E, Lee ZD, True LD, Yun TJ, Tondravi M and Vessella RL . (2001). Urology, 57, 611–616.
Byrd VM, Ballard DW, Miller GG and Thomas JW . (1999). J. Immunol., 162, 5853–5859.
Chen T, Carter D, Garrigue-Antar L and Reiss M . (1998). Cancer Res., 58, 4805–4810.
Chen T, de Vries EG, Hollema H, Yegen HA, Vellucci VF, Strickler HD, Hildesheim A and Reiss M . (1999). Int. J. Cancer, 82, 43–51.
Clauss M . (2000). Semin. Thromb. Hemost., 26, 561–569.
Coussens LM and Werb Z . (2001). J. Exp. Med., 193, 727–740.
Coward WR, Okayama Y, Sagara H, Wilson SJ, Holgate ST and Church MK . (2002). J. Immunol., 169, 5287–5293.
Deng J, Miller SA, Wang HY, Xia W, Wen Y, Zhou BP, Li Y, Lin SY and Hung MC . (2002). Cancer Cell, 2, 323–334.
Furudoi A, Tanaka S, Haruma K, Kitadai Y, Yoshihara M, Chayama K and Shimamoto F . (2002). Oncology, 62, 157–166.
Furuta K, Misao S, Takahashi K, Tagaya T, Fukuzawa Y, Ishikawa T, Yoshioka K and Kakumu S . (1999). Int. J. Cancer, 81, 851–853.
Galibert L, Tometsko ME, Anderson DM, Cosman D and Dougall WC . (1998). J. Biol. Chem., 273, 34120–34127.
Giri DK and Aggarwal BB . (1998). J. Biol. Chem., 273, 14008–14014.
Held-Feindt J and Mentlein R . (2002). Int. J. Cancer, 98, 352–356.
Hermouet S, Corre I and Lippert E . (2000). Leuk. Lymphoma, 38, 39–48.
Hishima T, Fukayama M, Hayashi Y, Fujii T, Ooba T, Funata N and Koike M . (2000). Am. J. Surg. Pathol., 24, 742–746.
Iacopetta BJ, Soong R, House AK and Hamelin R . (1999). J. Pathol., 187, 428–432.
Kacinski BM . (1995). Ann. Med., 27, 79–85.
Karkkainen MJ, Makinen T and Alitalo K . (2002). Nat. Cell Biol., 4, E2–E5.
Karkkainen MJ and Petrova TV . (2000). Oncogene, 19, 5598–5605.
Kascinski B . (2002). Cancer Treat. Res., 107, 285–292.
Klomp HJ, Zernial O, Flachmann S, Wellstein A and Juhl H . (2002). Clin. Cancer Res., 8, 823–827.
Kornmann M, Ishiwata T, Beger HG and Korc M . (1997). Oncogene, 15, 1417–1424.
Koubek K, Stary J, Kumberova A, Klamova H and Filipec M . (1999). Eur. J. Haematol., 63, 1–10.
Li JM, Shen X, Hu PP and Wang XF . (1998). Mol. Cell. Biol., 18, 110–121.
Lu T, Burdelya LG, Swiatkowski SM, Boiko AD, Howe PH, Stark GR and Gudkov AV, manuscript submitted.
Mattila MM, Ruohola JK, Karpanen T, Jackson DG, Alitalo K and Harkonen PL . (2002). Int. J. Cancer, 98, 946–951.
McDermott RS, Deneux L, Mosseri V, Vedrenne J, Clough K, Fourquet A, Rodriguez J, Cosset JM, Sastre X, Beuzeboc P, Pouillart P and Scholl SM . (2002). Eur. Cytokine Network, 13, 121–127.
Mentlein R and Held-Feindt J . (2002). J. Neurochem., 83, 747–753.
Michigami T, Ihara-Watanabe M, Yamazaki M and Ozono K . (2001). Cancer Res., 61, 1637–1644.
Miyaki M, Iijima T, Konishi M, Sakai K, Ishii A, Yasuno M, Hishima T, Koike M, Shitara N, Iwama T, Utsunomiya J, Kuroki T and Mori T . (1999). Oncogene, 18, 3098–3103.
Mizukami J, Takaesu G, Akatsuka H, Sakurai H, Ninomiya-Tsuji J, Matsumoto K and Sakurai N . (2002). Mol. Cell. Biol., 22, 992–1000.
O'Connell MA, Cleere R, Long A, O'Neill LA and Kelleher D . (1995). J. Biol. Chem., 270, 7399–7404.
O'Neill LA . (2002). Mol. Cell, 10, 969–971.
Pahl HL . (1999). Oncogene, 18, 6853–6866.
Romieu-Mourez R, Landesman-Bollag E, Seldin DC and Sonenshein GE . (2002). Cancer Res., 62, 6770–6778.
Roux S, Amazit L, Meduri G, Guiochon-Mantel A, Milgrom E and Mariette X . (2002). Am. J. Clin. Pathol., 117, 210–216.
Sapi E and Kacinski BM . (1999). Proc. Soc. Exp. Biol. Med., 220, 1–8.
Sathe SS, Sizemore N, Li X, Vithalani K, Commane M, Swiatkowski SM and Stark GR, manuscript submitted.
Schiemann WP, Pfeifer WM, Levi E, Kadin ME and Lodish HF . (1999). Blood, 94, 2854–2861.
Sezer O, Heider U, Jakob C, Zavrski I, Eucker J, Possinger K, Sers C and Krenn V . (2002). Blood, 99, 4646–4647.
Siebenlist U, Franzoso G and Brown K . (1994). Annu. Rev. Cell Biol., 10, 405–455.
Sizemore N, Lerner N, Dombrowski N, Sakurai H and Stark G . (2002). J. Biol. Chem., 277, 3863–3869.
Takahashi A, Kono K, Itakura J, Amemiya H, Feng TR, Iizuka H, Fujii H and Matsumoto Y . (2002). Oncology, 62, 121–127.
Ueda M, Terai Y, Yamashita Y, Kumagai K, Ueki K, Yamaguchi H, Akise D, Hung YC and Ueki M . (2002). Int. J. Cancer, 98, 335–343.
Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D and Miyamoto S . (1995). Genes Dev., 9, 2723–2735.
Wolf JS, Chen Z, Dong G, Sunwoo JB, Bancroft CC, Capo DE, Yeh NT, Mukaida N and Van Waes C . (2001). Clin. Cancer Res., 7, 1812–1820.
Xing L, Bushnell TP, Carlson L, Tai Z, Tondravi M, Siebenlist U, Young F and Boyce BF . (2002). J. Bone Miner. Res., 17, 1200–1210.
Yamamoto H, Kishimoto T and Minamoto S . (1998). J. Immunol., 161, 4753–4759.
Yonemura Y, Endo Y, Fujita H, Fushida S, Ninomiya I, Bandou E, Taniguchi K, Miwa K, Ohoyama S, Sugiyama K and Sasaki T . (1999). Clin. Cancer Res., 5, 1823–1829.
Zhang N, Zhong R and Deuel TF . (1999). J. Biol. Chem., 274, 12959–12962.
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Lu, T., Sathe, S., Swiatkowski, S. et al. Secretion of cytokines and growth factors as a general cause of constitutive NFκB activation in cancer. Oncogene 23, 2138–2145 (2004). https://doi.org/10.1038/sj.onc.1207332
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DOI: https://doi.org/10.1038/sj.onc.1207332
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