TNF potentiates anticancer activity of bortezomib (Velcade®) through reduced expression of proteasome subunits and dysregulation of unfolded protein response
Dominika Nowis
Department of Anatomy and Cell Biology, Indiana University School of Medicine–Evansville, 8600 University Boulevard, Evansville, IN
Dominika Nowis: On leave from the Department of Immunology, Center of Biostructure, Medical University of Warsaw, Warsaw, Poland.
Search for more papers by this authorElizabeth J. McConnell
Department of Anatomy and Cell Biology, Indiana University School of Medicine–Evansville, 8600 University Boulevard, Evansville, IN
Search for more papers by this authorLindsey Dierlam
Department of Anatomy and Cell Biology, Indiana University School of Medicine–Evansville, 8600 University Boulevard, Evansville, IN
Search for more papers by this authorAlla Palamarchuk
Department of Anatomy and Cell Biology, Indiana University School of Medicine–Evansville, 8600 University Boulevard, Evansville, IN
Search for more papers by this authorAgnieszka Lass
Department of Anatomy and Cell Biology, Indiana University School of Medicine–Evansville, 8600 University Boulevard, Evansville, IN
Search for more papers by this authorCorresponding Author
Cezary Wójcik
Department of Anatomy and Cell Biology, Indiana University School of Medicine–Evansville, 8600 University Boulevard, Evansville, IN
Fax: +1-812-4651184.
Department of Anatomy and Cell Biology, Indiana University School of Medicine–Evansville, 8600 University Boulevard, Evansville, IN 47712, USASearch for more papers by this authorDominika Nowis
Department of Anatomy and Cell Biology, Indiana University School of Medicine–Evansville, 8600 University Boulevard, Evansville, IN
Dominika Nowis: On leave from the Department of Immunology, Center of Biostructure, Medical University of Warsaw, Warsaw, Poland.
Search for more papers by this authorElizabeth J. McConnell
Department of Anatomy and Cell Biology, Indiana University School of Medicine–Evansville, 8600 University Boulevard, Evansville, IN
Search for more papers by this authorLindsey Dierlam
Department of Anatomy and Cell Biology, Indiana University School of Medicine–Evansville, 8600 University Boulevard, Evansville, IN
Search for more papers by this authorAlla Palamarchuk
Department of Anatomy and Cell Biology, Indiana University School of Medicine–Evansville, 8600 University Boulevard, Evansville, IN
Search for more papers by this authorAgnieszka Lass
Department of Anatomy and Cell Biology, Indiana University School of Medicine–Evansville, 8600 University Boulevard, Evansville, IN
Search for more papers by this authorCorresponding Author
Cezary Wójcik
Department of Anatomy and Cell Biology, Indiana University School of Medicine–Evansville, 8600 University Boulevard, Evansville, IN
Fax: +1-812-4651184.
Department of Anatomy and Cell Biology, Indiana University School of Medicine–Evansville, 8600 University Boulevard, Evansville, IN 47712, USASearch for more papers by this authorAbstract
Bortezomib (Velcade®) exploits proteasome inhibition as a unique mechanism of anticancer activity. The effectiveness of bortezomib is, however, limited, therefore, the search for therapeutic regimens combining bortezomib with other agents. In the present work we demonstrate enhanced anticancer activity of bortezomib by its combination with tumor necrosis factor (TNF) in the experimental model of C-26 colon carcinoma in mice. This interaction likely relies on the induction of a dysregulated response to ER stress, leading to apoptosis of cancer cells, evidenced by caspase-3 cleavage, p53 accumulation as well as increased SAPK/JNK phosphorylation. ER stress induced by the combination of TNF and bortezomib is corroborated by upregulation of BiP, PDI and calnexin as well as cleavage of caspase-12; however, in contrast to the classic pathway, it is also associated with decreased phosphorylation of eIF2α and prevention of XBP-1 splicing. TNF prevented the upregulation of Hsp27 induced by bortezomib, which may contribute to enhanced ER stress. Moreover, TNF interfered with bortezomib-induced upregulation of distinct subunits of the 26S proteasome. Bortezomib concentration used in this study was not sufficient to prevent TNF from inducing nuclear translocation of p65/RelA; however, the combination of both agents reduced total p65/RelA levels. Combined treatment of tumor-bearing mice with bortezomib and TNF not only inhibited tumor growth but also significantly prolonged animal survival. Therefore, combination of bortezomib with TNF is an attractive option for further clinical studies. © 2007 Wiley-Liss, Inc.
References
- 1 Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 2002; 82: 373–428.
- 2 Joazeiro CAP, Anderson KC, Hunter T. Proteasome inhibitor drugs on the rise. Cancer Res 2006; 66: 7840–42.
- 3 Adams J. The development of proteasome inhibitors as anticancer drugs. Cancer Cell 2004; 5: 417–21.
- 4 Kisselev AF, Goldberg AL. Proteasome inhibitors: from research tools to drug candidates. Chem Biol 2001; 8: 739–58.
- 5 Wojcik C, Stoklosa T, Giermasz A, Golab J, Zagozdzon R, Kawiak J, Wilk S, Komar A, Kaca A, Malejczyk J, Jakobisiak M. Apoptosis induced in L1210 leukaemia cells by an inhibitor of the chymotrypsin-like activity of the proteasome. Apoptosis 1997; 2: 455–62.
- 6 Shinohara K, Tomioka M, Nakano H, Tone S, Ito H, Kawashima S. Apoptosis induction resulting from proteasome inhibition. Biochem J 1996; 317 (Part 2): 385–8.
- 7 Wojcik C, Schroeter D, Stoehr M, Wilk S, Paweletz N. An inhibitor of the chymotrypsin-like activity of the multicatalytic proteinase complex (20S proteasome) induces arrest in G2-phase and metaphase in HeLa cells. Eur J Cell Biol 1996; 70: 172–8.
- 8 Imajoh-Ohmi S, Kawaguchi T, Sugiyama S, Tanaka K, Omura S, Kikuchi H. Lactacystin, a specific inhibitor of the proteasome, induces apoptosis in human monoblast U937 cells. Biochem Biophys Res Commun 1995; 217: 1070–7.
- 9 Orlowski RZ, Eswara JR, Lafond-Walker A, Grever MR, Orlowski M, Dang CV. Tumor growth inhibition induced in a murine model of human Burkitt's lymphoma by a proteasome inhibitor. Cancer Res 1998; 58: 4342–8.
- 10 Stoklosa T, Golab J, Wójcik C, Jalili A, Marczak M, Giermasz A, Januszko P, Balkowiec E, Jakóbisiak M, Wilk S. Antitumor effect of proteasome inhibitor dependent on p53 induction and angiogenesis inhibition, Third Workshop on Proteasomes, Clermont-Ferrand, France, March 24, 1999.
- 11 Shah SA, Potter MW, McDade TP, Ricciardi R, Perugini RA, Elliott PJ, Adams J, Callery MP. 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J Cell Biochem 2001; 82: 110–22.
- 12 Amiri KI, Horton LW, LaFleur BJ, Sosman JA, Richmond A. Augmenting chemosensitivity of malignant melanoma tumors via proteasome inhibition: implication for bortezomib (VELCADE, PS-341) as a therapeutic agent for malignant melanoma. Cancer Res 2004; 64: 4912–18.
- 13 Yin D, Zhou H, Kumagai T, Liu G, Ong JM, Black KL, Koeffler HP. Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM). Oncogene 2005; 24: 344–54.
- 14 Chauhan D, Li G, Shringarpure R, Podar K, Ohtake Y, Hideshima T, Anderson KC. Blockade of Hsp27 overcomes Bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res 2003; 63: 6174–7.
- 15 Jones DR, Broad RM, Comeau LD, Parsons SJ, Mayo MW. Inhibition of nuclear factor κB chemosensitizes non-small cell lung cancer through cytochrome c release and caspase activation. J Thorac Cardiovasc Surg 2002; 123: 310–17.
- 16 Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao PJ. The nuclear factor-κB RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 1999; 5: 119–27.
- 17 Aghajanian C, Dizon DS, Sabbatini P, Raizer JJ, Dupont J, Spriggs DR. Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer. J Clin Oncol 2005; 23: 5943–9.
- 18 Messersmith WA, Baker SD, Lassiter L, Sullivan RA, Dinh K, Almuete VI, Wright JJ, Donehower RC, Carducci MA, Armstrong DK. Phase I trial of bortezomib in combination with docetaxel in patients with advanced solid tumors. Clin Cancer Res 2006; 12: 1270–5.
- 19 David E, Sun SY, Waller EK, Chen J, Khuri FR, Lonial S. The combination of the Farnesyl transferase inhibitor (Lonafarnib) and the proteasome inhibitor (Bortezomib) induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT. Blood 2005; 106: 4322–29.
- 20 Bold RJ, Virudachalam S, McConkey DJ. Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome. J Surg Res 2001; 100: 11–17.
- 21 Minami T, Adachi M, Kawamura R, Zhang Y, Shinomura Y, Imai K. Sulindac enhances the proteasome inhibitor bortezomib-mediated oxidative stress and anticancer activity. Clin Cancer Res 2005; 11: 5248–56.
- 22 Russo SM, Tepper JE, Baldwin AS,Jr, Liu R, Adams J, Elliott P, Cusack JC,Jr. Enhancement of radiosensitivity by proteasome inhibition: implications for a role of NF-κB. Int J Radiat Oncol Biol Phys 2001; 50: 183–93.
- 23 Nawrocki ST, Carew JS, Pino MS, Highshaw RA, Andtbacka RH, Dunner K,Jr, Pal A, Bornmann WG, Chiao PJ, Huang P, Xiong H, Abbruzzese JL, et al. Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res 2006; 66: 3773–81.
- 24 Mocellin S, Rossi CR, Pilati P, Nitti D. Tumor necrosis factor, cancer and anticancer therapy. Cytokine Growth Factor Rev 2005; 16: 35–53.
- 25 Lans TE, Grunhagen DJ, de Wilt JH, van Geel AN, Eggermont AM. Isolated limb perfusions with tumor necrosis factor and melphalan for locally recurrent soft tissue sarcoma in previously irradiated limbs. Ann Surg Oncol 2005; 12: 406–11.
- 26 Noorda EM, Vrouenraets BC, Nieweg OE, van Geel BN, Eggermont AM, Kroon BB. Isolated limb perfusion for unresectable melanoma of the extremities. Arch Surg 2004; 139: 1237–42.
- 27 Alexander HR,Jr, Libutti SK, Bartlett DL, Pingpank JF, Kranda K, Helsabeck C, Beresnev T. Hepatic vascular isolation and perfusion for patients with progressive unresectable liver metastases from colorectal carcinoma refractory to previous systemic and regional chemotherapy. Cancer 2002; 95: 730–6.
- 28 Corti A, Ponzoni M. Tumor vascular targeting with tumor necrosis factor α and chemotherapeutic drugs. Ann NY Acad Sci 2004; 1028: 104–12.
- 29 Buell JF, Reed E, Lee KB, Parker RJ, Venzon DJ, Amikura K, Arnold S, Fraker DL, Alexander HR. Synergistic effect and possible mechanisms of tumor necrosis factor and cisplatin cytotoxicity under moderate hyperthermia against gastric cancer cells. Ann Surg Oncol 1997; 4: 141–8.
- 30 Manusama ER, Nooijen PT, Stavast J, Durante NM, Marquet RL, Eggermont AM. Synergistic antitumour effect of recombinant human tumour necrosis factor α with melphalan in isolated limb perfusion in the rat. Br J Surg 1996; 83: 551–5.
- 31 Seynhaeve AL, de Wilt JH, van Tiel ST, Eggermont AM, ten Hagen TL. Isolated limb perfusion with actinomycin D and TNF-α results in improved tumour response in soft-tissue sarcoma-bearing rats but is accompanied by severe local toxicity. Br J Cancer 2002; 86: 1174–9.
- 32 Wang CY, Mayo MW, Baldwin AS,Jr. TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-κB. Science 1996; 274: 784–7.
- 33 Stoklosa T, Wojcik C, Golab J, Giermasz A, Wilk S. Inhibition of proteasome, apoptosis and sensitization to tumour necrosis factor α: do they always go together? Br J Cancer 1999; 79: 375–6.
- 34 Delic J, Masdehors P, Omura S, Cosset JM, Dumont J, Binet JL, Magdelenat H. The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-α-initiated apoptosis. Br J Cancer 1998; 77: 1103–7.
- 35 Golab J, Stoklosa T, Czajka A, Dabrowska A, Jakobisiak M, Zagozdzon R, Wojcik C, Marczak M, Wilk S. Synergistic antitumor effects of a selective proteasome inhibitor and TNF in mice. Anticancer Res 2000; 20: 1717–21.
- 36 Corbett TH, Polin L, Roberts BJ, Lawson AJ, Leopold WR, White K, Kushner J, Paluch J, Hazeldine S, Moore R, Rake J, Horwitz JP. Transplantable syngeneic rodent tumors: solid tumors in mice. In: BA Teicher, ed. Tumor models in animal research. Totowa, New Jersey: Humana Press, 2002. 41–72.
- 37 Corbett TH, Roberts BJ, Leopold WR, Peckham JC, Wilkoff LJ, Griswold DP,Jr, Schabel FM,Jr. Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL/6 mice. Cancer Res 1984; 44: 717–26.
- 38 Wilk S, Orlowski M. Cation-sensitive neutral endopeptidase: isolation and specificity of the bovine pituitary enzyme. J Neurochem 1980; 35: 1172–82.
- 39 Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 2001; 107: 881–91.
- 40 Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984; 22: 27–55.
- 41 Nawrocki ST, Carew JS, Pino MS, Highshaw RA, Dunner K,Jr, Huang P, Abbruzzese JL, McConkey DJ. Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis. Cancer Res 2005; 65: 11658–66.
- 42 Nawrocki ST, Carew JS, Dunner K,Jr, Boise LH, Chiao PJ, Huang P, Abbruzzese JL, McConkey DJ. Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. Cancer Res 2005; 65: 11510–9.
- 43 Lee AH, Iwakoshi NN, Anderson KC, Glimcher LH. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci USA 2003; 100: 9946–51.
- 44 Boyce M, Yuan J. Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ 2006; 13: 363–73.
- 45 Wojcik C, Rowicka M, Kudlicki A, Nowis D, McConnell E, Kujawa M, DeMartino GN. Valosin-containing protein (p97) is a regulator of ER stress and of the degradation of N-end rule and Ubiquitin-fusion degradation pathway substrates in mammalian cells. Mol Biol Cell 2006; 17: 4606–18.
- 46 Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, Yuan J. A selective inhibitor of eIF2α dephosphorylation protects cells from ER stress. Science 2005; 307: 935–9.
- 47 Wojcik C, Schroeter D, Wilk S, Lamprecht J, Paweletz N. Ubiquitin-mediated proteolysis centers in HeLa cells: indication from studies of an inhibitor of the chymotrypsin-like activity of the proteasome. Eur J Cell Biol 1996; 71: 311–18.
- 48 Meiners S, Heyken D, Weller A, Ludwig A, Stangl K, Kloetzel PM, Kruger E. Inhibition of proteasome activity induces concerted expression of proteasome genes and de novo formation of Mammalian proteasomes. J Biol Chem 2003; 278: 21517–25.
- 49 Romisch K. Endoplasmic reticulum-associated degradation. Annu Rev Cell Dev Biol 2005; 21: 435–56.
- 50 Obeng EA, Carlson LM, Gutman DM, Harrington WJ,Jr, Lee KP, Boise LH. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 2006; 107: 4907–16.
- 51 Parcellier A, Schmitt E, Gurbuxani S, Seigneurin-Berny D, Pance A, Chantome A, Plenchette S, Khochbin S, Solary E, Garrido C. HSP27 is a ubiquitin-binding protein involved in I-κBα proteasomal degradation. Mol Cell Biol 2003; 23: 5790–802.
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