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Proteotoxic Stress and Proteasome Inhibitor Efficacy and Resistance

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Resistance to Proteasome Inhibitors in Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT))

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Abstract

Proteasome inhibitors have established themselves as the frontline therapy for multiple myeloma (MM) and they are displaying strong clinical activity in a variety of other hematological cancers. However, as is observed with other targeted agents, resistance to proteasome inhibitor therapy is emerging as a major clinical challenge. Accumulating evidence has implicated proteotoxicity in the cytotoxic mechanisms of proteasome inhibitors in cancer cells, and it is therefore not surprising that key resistance mechanisms involve inducible, physiological cytoprotective responses to proteotoxicity. Here I will discuss our current understanding of the role of proteotoxicity in the antitumor activities of proteasome inhibitors and the evidence that induced cytoprotective mechanisms could play important roles in mediating resistance.

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Abbreviations

ATF:

Activating transcription factor

ATG:

Autophagy-related gene

CHOP:

C/EBP-homologous protein

ER:

Endoplasmic reticulum

GADD:

Growth arrest and DNA damage-induced

GCN2:

General control nonderepressible 2 kinase

Grp:

Glucose-regulated protein

HDAC:

Histone deacetylase

HRI:

Heme-regulated inhibitor

HSP:

Heat shock protein

ISR:

Integrated stress response

IκBα:

Inhibitor of nuclear factor kappa B, alpha isoform

LC3:

Microtubule-associated protein light chain 3

MEF:

Mouse embryonic fibroblast

MM:

Multiple myeloma

NF-κB:

Nuclear factor kappa B

PERK:

Pancreatic ER kinase

PKR:

Protein kinase R

ROS:

Reactive oxygen species

UPR:

Unfolded protein response

XBP-1:

X-box binding protein-1

References

  1. Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD et al (1999) Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59(11):2615–2622, Epub 1999/06/11

    PubMed  CAS  Google Scholar 

  2. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T et al (2002) NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 277(19):16639–16647, Epub 2002/03/02

    Article  PubMed  CAS  Google Scholar 

  3. Williams SA, McConkey DJ (2003) The proteasome inhibitor bortezomib stabilizes a novel active form of p53 in human LNCaP-Pro5 prostate cancer cells. Cancer Res 63(21):7338–7344, Epub 2003/11/13

    PubMed  CAS  Google Scholar 

  4. Sunwoo JB, Chen Z, Dong G, Yeh N, Crowl Bancroft C, Sausville E et al (2001) Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Cancer Res 7(5):1419–28, Epub 2001/05/15

    PubMed  CAS  Google Scholar 

  5. Nawrocki ST, Bruns CJ, Harbison MT, Bold RJ, Gotsch BS, Abbruzzese JL et al (2002) Effects of the proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic human pancreatic tumor xenografts. Mol Cancer Ther 1(14):1243–1253, Epub 2003/01/09

    PubMed  CAS  Google Scholar 

  6. Zhu K, Chan W, Heymach J, Wilkinson M, McConkey DJ (2009) Control of HIF-1alpha expression by eIF2 alpha phosphorylation-mediated translational repression. Cancer Res 69(5):1836–1843, Epub 2009/02/27

    Article  PubMed  CAS  Google Scholar 

  7. Williams S, Pettaway C, Song R, Papandreou C, Logothetis C, McConkey DJ (2003) Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts. Mol Cancer Ther 2(9):835–843, Epub 2003/10/14

    PubMed  CAS  Google Scholar 

  8. Adams J (2004) The development of proteasome inhibitors as anticancer drugs. Cancer Cell 5(5):417–421, Epub 2004/05/18

    Article  PubMed  CAS  Google Scholar 

  9. Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S et al (2002) Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 20(22):4420–4427, Epub 2002/11/15

    Article  PubMed  CAS  Google Scholar 

  10. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348(26):2609–2617, Epub 2003/06/27

    Article  PubMed  CAS  Google Scholar 

  11. Twombly R (2003) First proteasome inhibitor approved for multiple myeloma. J Natl Cancer Inst 95(12):845, Epub 2003/06/19

    Article  PubMed  Google Scholar 

  12. Kane RC, Bross PF, Farrell AT, Pazdur R (2003) Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 8(6):508–513

    Article  PubMed  Google Scholar 

  13. Kuhn DJ, Chen Q, Voorhees PM, Strader JS, Shenk KD, Sun CM et al (2007) Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 110(9):3281–3290, Epub 2007/06/27

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Chauhan D, Catley L, Li G, Podar K, Hideshima T, Velankar M et al (2005) A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 8(5):407–419, Epub 2005/11/16

    Article  PubMed  CAS  Google Scholar 

  15. Katsnelson A (2012) Next-generation proteasome inhibitor approved in multiple myeloma. Nat Biotechnol 30(11):1011–1012, Epub 2012/11/10

    Article  PubMed  CAS  Google Scholar 

  16. Herndon TM, Deisseroth A, Kaminskas E, Kane RC, Koti KM, Rothmann MD et al (2013) U.S. Food and Drug Administration approval: carfilzomib for the treatment of multiple myeloma. Clin Cancer Res 19(17):4559–4563

    Article  PubMed  CAS  Google Scholar 

  17. Smith MH, Ploegh HL, Weissman JS (2011) Road to ruin: targeting proteins for degradation in the endoplasmic reticulum. Science 334(6059):1086–1090, Epub 2011/11/26

    Article  PubMed  CAS  Google Scholar 

  18. Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH (2006) Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 107(12):4907–4916, Epub 2006/03/02

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Schewe DM, Aguirre-Ghiso JA (2009) Inhibition of eIF2alpha dephosphorylation maximizes bortezomib efficiency and eliminates quiescent multiple myeloma cells surviving proteasome inhibitor therapy. Cancer Res 69(4):1545–1552, Epub 2009/02/05

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Meister S, Schubert U, Neubert K, Herrmann K, Burger R, Gramatzki M et al (2007) Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res 67(4):1783–1792, Epub 2007/02/20

    Article  PubMed  CAS  Google Scholar 

  21. Hightower LE (1991) Heat shock, stress proteins, chaperones, and proteotoxicity. Cell 66(2):191–197, Epub 1991/07/26

    Article  PubMed  CAS  Google Scholar 

  22. Morimoto RI (2011) The heat shock response: systems biology of proteotoxic stress in aging and disease. Cold Spring Harb Symp Quant Biol 76:91–9, Epub 2012/03/01

    Article  PubMed  CAS  Google Scholar 

  23. Morimoto RI (1993) Cells in stress: transcriptional activation of heat shock genes. Science 259(5100):1409–1410, Epub 1993/03/05

    Article  PubMed  CAS  Google Scholar 

  24. Westerheide SD, Morimoto RI (2005) Heat shock response modulators as therapeutic tools for diseases of protein conformation. J Biol Chem 280(39):33097–33100, Epub 2005/08/04

    Article  PubMed  CAS  Google Scholar 

  25. Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 426(6968):895–899, Epub 2003/12/20

    Article  PubMed  CAS  Google Scholar 

  26. McConkey DJ, White M, Yan W (2012) HDAC inhibitor modulation of proteotoxicity as a therapeutic approach in cancer. Adv Cancer Res 116:131–163, Epub 2012/10/24

    Article  PubMed  CAS  Google Scholar 

  27. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M et al (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6(5):1099–1108, Epub 2000/12/07

    Article  PubMed  CAS  Google Scholar 

  28. Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5(5):897–904, Epub 2000/07/06

    Article  PubMed  CAS  Google Scholar 

  29. Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397(6716):271–274, Epub 1999/02/04

    Article  PubMed  CAS  Google Scholar 

  30. Shi Y, Vattem KM, Sood R, An J, Liang J, Stramm L et al (1998) Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol 18(12):7499–7509, Epub 1998/11/20

    PubMed  CAS  PubMed Central  Google Scholar 

  31. Evan G, Harrington E, Fanidi A, Land H, Amati B, Bennett M (1994) Integrated control of cell proliferation and cell death by the c-myc oncogene. Philos Trans R Soc Lond B Biol Sci 345(1313):269–275, Epub 1994/08/30

    Article  PubMed  CAS  Google Scholar 

  32. Harrington EA, Fanidi A, Evan GI (1994) Oncogenes and cell death. Curr Opin Genet Dev 4(1):120–129, Epub 1994/02/01

    Article  PubMed  CAS  Google Scholar 

  33. Zhu K, Dunner K Jr, McConkey DJ (2010) Proteasome inhibitors activate autophagy as a cytoprotective response in human prostate cancer cells. Oncogene 29(3):451–462, Epub 2009/11/03

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Talloczy Z, Jiang W, Virgin HW 4th, Leib DA, Scheuner D, Kaufman RJ et al (2002) Regulation of starvation- and virus-induced autophagy by the eIF2alpha kinase signaling pathway. Proc Natl Acad Sci U S A 99(1):190–5, Epub 2002/01/05

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Rouschop KM, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K et al (2010) The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest 120(1):127–141, Epub 2009/12/30

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Jiang HY, Wek RC (2005) Phosphorylation of the alpha-subunit of the eukaryotic initiation factor-2 (eIF2alpha) reduces protein synthesis and enhances apoptosis in response to proteasome inhibition. J Biol Chem 280(14):14189–14202, Epub 2005/02/03

    Article  PubMed  CAS  Google Scholar 

  37. Suraweera A, Munch C, Hanssum A, Bertolotti A (2012) Failure of amino acid homeostasis causes cell death following proteasome inhibition. Mol Cell 48(2):242–253, Epub 2012/09/11

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Nawrocki ST, Carew JS, Dunner K Jr, Boise LH, Chiao PJ, Huang P et al (2005) Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. Cancer Res 65(24):11510–11519, Epub 2005/12/17

    Article  PubMed  CAS  Google Scholar 

  39. Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R et al (2004) CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 18(24):3066–3077, Epub 2004/12/17

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Yerlikaya A, Kimball SR, Stanley BA (2008) Phosphorylation of eIF2alpha in response to 26S proteasome inhibition is mediated by the haem-regulated inhibitor (HRI) kinase. Biochem J 412(3):579–588, Epub 2008/02/23

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Nawrocki ST, Carew JS, Maclean KH, Courage JF, Huang P, Houghton JA et al (2008) Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA. Blood 112(7):2917–2926, Epub 2008/07/22

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Nawrocki ST, Carew JS, Pino MS, Highshaw RA, Andtbacka RH, Dunner K Jr et al (2006) Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res 66(7):3773–3781, Epub 2006/04/06

    Article  PubMed  CAS  Google Scholar 

  43. Hideshima T, Bradner JE, Wong J, Chauhan D, Richardson P, Schreiber SL et al (2005) Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci U S A 102(24):8567–8572, Epub 2005/06/07

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Johnston JA, Ward CL, Kopito RR (1998) Aggresomes: a cellular response to misfolded proteins. J Cell Biol 143(7):1883–1898, Epub 1998/12/29

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  45. Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP (2003) The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115(6):727–738, Epub 2003/12/17

    Article  PubMed  CAS  Google Scholar 

  46. Chandra J (2009) Oxidative stress by targeted agents promotes cytotoxicity in hematologic malignancies. Antioxid Redox Signal 11(5):1123–1137, Epub 2008/11/21

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Miller CP, Ban K, Dujka ME, McConkey DJ, Munsell M, Palladino M et al (2007) NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells. Blood 110(1):267–277, Epub 2007/03/16

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  48. Pei XY, Dai Y, Grant S (2004) Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin Cancer Res 10(11):3839–3852, Epub 2004/06/03

    Article  PubMed  CAS  Google Scholar 

  49. Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S (2003) The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Blood 102(10):3765–3774, Epub 2003/08/02

    Article  PubMed  CAS  Google Scholar 

  50. Yu C, Rahmani M, Dent P, Grant S (2004) The hierarchical relationship between MAPK signaling and ROS generation in human leukemia cells undergoing apoptosis in response to the proteasome inhibitor Bortezomib. Exp Cell Res 295(2):555–566, Epub 2004/04/20

    Article  PubMed  CAS  Google Scholar 

  51. Qi W, White MC, Choi W, Guo C, Dinney C, McConkey DJ et al (2013) Inhibition of inducible heat shock protein-70 (hsp72) enhances bortezomib-induced cell death in human bladder cancer cells. PLoS One 8(7):e69509, Epub 2013/07/23

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. Sorolla A, Yeramian A, Dolcet X, Perez de Santos AM, Llobet D, Schoenenberger JA et al (2008) Effect of proteasome inhibitors on proliferation and apoptosis of human cutaneous melanoma-derived cell lines. Br J Dermatol 158(3):496–504, Epub 2008/01/22

    Article  PubMed  CAS  Google Scholar 

  53. Gu H, Chen X, Gao G, Dong H (2008) Caspase-2 functions upstream of mitochondria in endoplasmic reticulum stress-induced apoptosis by bortezomib in human myeloma cells. Mol Cancer Ther 7(8):2298–2307, Epub 2008/08/30

    Article  PubMed  CAS  Google Scholar 

  54. Canfield SE, Zhu K, Williams SA, McConkey DJ (2006) Bortezomib inhibits docetaxel-induced apoptosis via a p21-dependent mechanism in human prostate cancer cells. Mol Cancer Ther 5(8):2043–2050, Epub 2006/08/25

    Article  PubMed  CAS  Google Scholar 

  55. Nawrocki ST, Sweeney-Gotsch B, Takamori R, McConkey DJ (2004) The proteasome inhibitor bortezomib enhances the activity of docetaxel in orthotopic human pancreatic tumor xenografts. Mol Cancer Ther 3(1):59–70, Epub 2004/01/30

    PubMed  CAS  Google Scholar 

  56. An B, Goldfarb RH, Siman R, Dou QP (1998) Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts. Cell Death Differ 5(12):1062–1075, Epub 1999/01/23

    Article  PubMed  CAS  Google Scholar 

  57. Brewer JW, Diehl JA (2000) PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc Natl Acad Sci U S A 97(23):12625–12630, Epub 2000/10/18

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  58. Lashinger LM, Zhu K, Williams SA, Shrader M, Dinney CP, McConkey DJ (2005) Bortezomib abolishes tumor necrosis factor-related apoptosis-inducing ligand resistance via a p21-dependent mechanism in human bladder and prostate cancer cells. Cancer Res 65(11):4902–4908, Epub 2005/06/03

    Article  PubMed  CAS  Google Scholar 

  59. Dasmahapatra G, Lembersky D, Son MP, Attkisson E, Dent P, Fisher RI et al (2011) Carfilzomib interacts synergistically with histone deacetylase inhibitors in mantle cell lymphoma cells in vitro and in vivo. Mol Cancer Ther 10(9):1686–1697, Epub 2011/07/14

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  60. Dasmahapatra G, Lembersky D, Kramer L, Fisher RI, Friedberg J, Dent P et al (2010) The pan-HDAC inhibitor vorinostat potentiates the activity of the proteasome inhibitor carfilzomib in human DLBCL cells in vitro and in vivo. Blood 115(22):4478–4487, Epub 2010/03/18

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  61. Dai Y, Chen S, Kramer LB, Funk VL, Dent P, Grant S (2008) Interactions between bortezomib and romidepsin and belinostat in chronic lymphocytic leukemia cells. Clin Cancer Res 14(2):549–558, Epub 2008/01/29

    Article  PubMed  CAS  Google Scholar 

  62. Millward M, Price T, Townsend A, Sweeney C, Spencer A, Sukumaran S et al (2012) Phase 1 clinical trial of the novel proteasome inhibitor marizomib with the histone deacetylase inhibitor vorinostat in patients with melanoma, pancreatic and lung cancer based on in vitro assessments of the combination. Invest New Drugs 30(6):2303–2317, Epub 2011/11/15

    Article  PubMed  CAS  Google Scholar 

  63. Amaravadi RK, Lippincott-Schwartz J, Yin XM, Weiss WA, Takebe N, Timmer W et al (2011) Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res 17(4):654–666, Epub 2011/02/18

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  64. Ding WX, Ni HM, Gao W, Yoshimori T, Stolz DB, Ron D et al (2007) Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol 171(2):513–524, Epub 2007/07/11

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  65. Ding WX, Ni HM, Gao W, Chen X, Kang JH, Stolz DB et al (2009) Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy. Mol Cancer Ther 8(7):2036–2045, Epub 2009/07/09

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  66. Leung-Hagesteijn C, Erdmann N, Cheung G, Keats JJ, Stewart AK, Reece DE et al (2013) Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma. Cancer Cell 24(3):289–304, Epub 2013/09/14

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  67. Kuhn DJ, Orlowski RZ (2012) The immunoproteasome as a target in hematologic malignancies. Semin Hematol 49(3):258–262, Epub 2012/06/26

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Departments of Urology and Cancer Biology, U.T. M.D. Anderson Cancer Center, Houston, TX, 77030, USA

    David McConkey

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  1. Wayne State University, Detroit, Michigan, USA

    Q. Ping Dou

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McConkey, D. (2014). Proteotoxic Stress and Proteasome Inhibitor Efficacy and Resistance. In: Dou, Q. (eds) Resistance to Proteasome Inhibitors in Cancer. Resistance to Targeted Anti-Cancer Therapeutics. Springer, Cham. https://doi.org/10.1007/978-3-319-06752-0_11

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