The endoplasmic reticulum and its signaling pathways – a novel target for multiple myeloma treatment

Česká verzia

Authors: A. Dostálová ¹; M. Vlachová ¹; J. Gregorová ¹; L. Moráň ^2,3; L. Pečinka ¹; V. Gabrielová ²; P. Vaňhara ^2,4; S. Ševčíková ^1,5
Authors place of work: Babákova myelomová skupina, Ústav patologické fyziologie, LF MU Brno ¹; Ústav histologie a embryologie, LF MU Brno ²; Výzkumné centrum aplikované molekulární onkologie (RECAMO), MOÚ Brno ³; Mezinárodní centrum klinického výzkumu, LF MU (ICRC) a FN u sv. Anny v Brně ⁴; Oddělení klinické hematologie, FN Brno ⁵
Published in the journal: Klin Onkol 2023; 37(6): 440-446
Category: Přehled
doi: https://doi.org/10.48095/ccko2023440

Summary

Background: The endoplasmic reticulum (ER), an organelle composed of a system of cisternae and tubules, is essential for many cellular processes, including protein synthesis and transport. When misfolded proteins accumulate in the ER lumen, ER stress is induced, and the subsequent response to the disruption of homeostasis is the activation of the unfolded protein response (UPR). The purpose of this process is to restore homeostasis by increasing the capacity of the ER and its ability to fold proteins. Activation of the homeostatic UPR occurs via one of three transmembrane proteins, inositol-requiring enzyme 1a (IRE1a), protein kinase R-like ER kinase (PERK) and activating transcription factor 6 (ATF6). Failure of the attempt to restore homeostasis, on the other hand, leads to the development of terminal UPR and apoptosis via hyperactivation of the same proteins. Activation of UPR has been described in many malignancies, including multiple myeloma (MM), which is characterized by malignant transformation of plasma cells and increased monoclonal immunoglobulin synthesis, where the role of the ER is of particular importance. Despite advances in the treatment of MM, the disease remains difficult to treat and targeting signaling pathways associated with the UPR could, for example, enhance the effect of proteasome inhibitors.

Purpose: This review intends to present the molecular response to ER stress under physiological circumstances and in the context of cancer, particularly with regard to potential therapeutic targets in MM.

Keywords:

Multiple myeloma – Endoplasmic reticulum – unfolded protein response

Zdroje

1. Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol 2020; 95 (5): 548–567. doi: 10.1002/ajh.25791.

2. Shibata Y, Shemesh T, Prinz WA et al. Mechanisms determining the morphology of the peripheral ER. Cell 2010; 143 (5): 774–788. doi: 10.1016/j.cell.2010.11.007.

3. Shibata Y, Voeltz GK, Rapoport TA. Rough sheets and smooth tubules. Cell 2006; 126 (3): 435–439. doi: 10.1016/j.cell.2006.07.019.

4. Watson ML. The nuclear envelope. J Biophys Biochem Cytol 1955; 1 (3): 257–270. doi: 10.1083/jcb.1.3.257.

5. Hetzer MW. The nuclear envelope. Cold Spring Harb Perspect Biol 2010; 2 (3): a000539. doi: 10.1101/cshperspect.a000539.

6. Hartl FU, Hayer-Hartl M. Converging concepts of protein folding in vitro and in vivo. Nat Struct Mol Biol 2009; 16 (6): 574–581. doi: 10.1038/nsmb.1591.

7. Ricci D, Gidalevitz T, Argon Y. The special unfolded protein response in plasma cells. Immunol Rev 2021; 303 (1): 35-51. doi: 10.1111/imr.13012.

8. Oakes SA, Papa FR. The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol 2015; 10: 173–194. doi: 10.1146/annurev-pathol-012513-104 649.

9. Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol 2020; 21 (8): 421–438. doi: 10.1038/s41580-020-0250-z.

10. Oakes SA. Endoplasmic reticulum stress signaling in cancer cells. Am J Pathol 2020; 190 (5): 934–946. doi: 10.1016/j.ajpath.2020.01.010.

11. Gardner BM, Walter P. Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response. Science 2011; 333 (6051): 1891–1894. doi: 10.1126/science.1209126.

12. Hollien J, Weissman JS. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 2006; 313 (5783): 104–107. doi: 10.1126/science.1129631.

13. Han J, Back SH, Hur J et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol 2013; 15 (5): 481–490. doi: 10.1038/ncb2738.

14. Hetz C, Papa FR. The unfolded protein response and cell fate control. Mol Cell 2018; 69 (2): 169–181. doi: 10.1016/j.molcel.2017.06.017.

15. Urra H, Dufey E, Lisbona F et al. When ER stress reaches a dead end. Biochim Biophys Acta 2013; 1833 (12): 3507–3517. doi: 10.1016/j.bbamcr.2013.07.024.

16. Lerner AG, Upton JP, Praveen PVK et al. IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab 2012; 16 (2): 250–264. doi: 10.1016/j.cmet.2012.07.007.

17. Koumenis C, Naczki C, Koritzinsky M et al. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol Cell Biol 2002; 22 (21): 7405–7416. doi: 10.1128/MCB.22.21.7405-7416.2002.

18. Zhang A, Zhang J, Sun P et al. EIF2α and caspase-12 activation are involved in oxygen-glucose-serum deprivation/restoration-induced apoptosis of spinal cord astrocytes. Neurosci Lett 2010; 478 (1): 32–36. doi: 10.1016/j.neulet.2010.04.062.

19. Yadav RK, Chae SW, Kim HR et al. Endoplasmic reticulum stress and cancer. J Cancer Prev 2014; 19 (2): 75–88. doi: 10.15430/JCP.2014.19.2.75.

20. Nakamura M, Gotoh T, Okuno Y et al. Activation of the endoplasmic reticulum stress pathway is associated with survival of myeloma cells. Leuk Lymphoma 2006; 47 (3): 531–539. doi: 10.1080/10428190500312196.

21. Schardt JA, Mueller BU, Pabst T. Activation of the unfolded protein response in human acute myeloid leukemia. Methods Enzymol 2011; 489: 227–243. doi: 10.1016/B978-0-12-385116-1.00013-3.

22. Balague O, Colomo L, Lopez-Guillermo A et al. Activation of the endoplasmic reticulum (ER) unfolded protein response (UPR) in aggressive B-cell lymphomas. Blood 2006; 108 (11): 2038. doi: 10.1182/blood.V108.11.2038.2038.

23. Scriven P, Coulson S, Haines R et al. Activation and clinical significance of the unfolded protein response in breast cancer. Br J Cancer 2009; 101 (10): 1692–1698. doi: 10.1038/sj.bjc.6605365.

24. Piton N, Wason J, Colasse É et al. Endoplasmic reticulum stress, unfolded protein response and development of colon adenocarcinoma. Virchows Arch Int J Pathol 2016; 469 (2): 145–154. doi: 10.1007/s00428-016-1961-6.

25. Fu W, Wu X, Li J et al. Upregulation of GRP78 in renal cell carcinoma and its significance. Urology 2010; 75 (3): 603–607. doi: 10.1016/j.urology.2009.05.007.

26. Shuda M, Kondoh N, Imazeki N et al. Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. J Hepatol 2003; 38 (5): 605–614. doi: 10.1016/s0168-8278 (03) 00029-1.

27. Wang Q, He Z, Zhang J et al. Overexpression of endoplasmic reticulum molecular chaperone GRP94 and GRP78 in human lung cancer tissues and its significance. Cancer Detect Prev 2005; 29 (6): 544–551. doi: 10.1016/j.cdp.2005.09.010.

28. Niu Z, Wang M, Zhou L et al. Elevated GRP78 expression is associated with poor prognosis in patients with pancreatic cancer. Sci Rep 2015; 5: 16067. doi: 10.1038/srep16067.

29. Niederreiter L, Fritz TMJ, Adolph TE et al. ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells. J Exp Med 2013; 210 (10): 2041–2056. doi: 10.1084/jem.20122341.

30. Wang Y, Alam GN, Ning Y et al. The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway. Cancer Res 2012; 72 (20): 5396–5406. doi: 10.1158/0008-5472.CAN-12- 0474.

31. Yan MM, Ni JD, Song D et al. Interplay between unfolded protein response and autophagy promotes tumor drug resistance. Oncol Lett 2015; 10 (4): 1959–1969. doi: 10.3892/ol.2015.3508.

32. Jiang X, Overholtzer M, Thompson CB. Autophagy in cellular metabolism and cancer. J Clin Invest 2015; 125 (1): 47–54. doi: 10.1172/JCI73942.

33. Nagelkerke A, Bussink J, Mujcic H et al. Hypoxia stimulates migration of breast cancer cells via the PERK/ATF4/LAMP3-arm of the unfolded protein response. Breast Cancer Res 2013; 15 (1): R2. doi: 10.1186/bcr3373.

34. Chaveroux C, Sarcinelli C, Barbet V et al. Nutrient shortage triggers the hexosamine biosynthetic pathway via the GCN2-ATF4 signalling pathway. Sci Rep 2016; 6: 27278. doi: 10.1038/srep27278.

35. Wang ZV, Deng Y, Gao N et al. Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway. Cell 2014; 156 (6): 1179–1192. doi: 10.1016/j.cell.2014.01.014.

36. Avril T, Vauléon E, Chevet E. Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers. Oncogenesis 2017; 6 (8): e373. doi: 10.1038/oncsis.2017.72.

37. Andruska N, Zheng X, Yang X et al. Anticipatory estrogen activation of the unfolded protein response is linked to cell proliferation and poor survival in estrogen receptor α-positive breast cancer. Oncogene 2015; 34 (29): 3760–3769. doi: 10.1038/onc.2014.292.

38. Reddy RK, Mao C, Baumeister P et al. Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation. Biol Chem 2003; 278 (23): 20915–20924. doi: 10.1074/jbc.M212328200.

39. Lee E, Nichols P, Spicer D et al. GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer. Cancer Res 2006; 66 (16): 7849–7853. doi: 10.1158/0008-5472.CAN-06-1660.

40. Salaroglio IC, Panada E, Moiso E et al. PERK induces resistance to cell death elicited by endoplasmic reticulum stress and chemotherapy. Mol Cancer 2017; 16 (1): 91. doi: 10.1186/s12943-017-0657-0.

41. Higa A, Taouji S, Lhomond S et al. Endoplasmic reticulum stress-activated transcription factor ATF6α requires the disulfide isomerase PDIA5 to modulate chemoresistance. Mol Cell Biol 2014; 34 (10): 1839–1849. doi: 10.1128/MCB.01484-13.

42. Marciniak SJ, Chambers JE, Ron D. Pharmacological targeting of endoplasmic reticulum stress in disease. Nat Rev Drug Discov 2022; 21 (2): 115–140. doi: 10.1038/s41573-021-00320-3.

43. Hetz C, Axten JM, Patterson JB. Pharmacological targeting of the unfolded protein response for disease intervention. Nat Chem Biol 2019; 15 (8): 764–775. doi: 10.1038/s41589-019-0326-2.

44. Papandreou I, Denko NC, Olson M et al. Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. Blood 2011; 117 (4): 1311–1314. doi: 10.1182/blood-2010-08-303099.

45. Kriss CL, Pinilla-Ibarz JA, Mailloux AW et al. Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice. Blood 2012; 120 (5): 1027–1038. doi: 10.1182/blood-2011-11-394346.

46. Zhao N, Cao J, Xu L et al. Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer. J Clin Invest 2018; 128 (4): 1283–1299. doi: 10.1172/JCI95873.

47. Axten JM, Medina JR, Feng Y et al. Discovery of 7-methyl-5- (1-{[3- (trifluoromethyl) phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl) -7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR) -like endoplasmic reticulum kinase (PERK). J Med Chem 2012; 55 (16): 7193–7207. doi: 10.1021/jm300713s.

48. Maluskova D, Svobodová I, Kucerova M et al. Epidemiology of multiple myeloma in the Czech Republic. Klin Onkol 2017; 30 (Suppl 2): 35–42. doi: 10.14735/amko20172S35.

49. Zhang K, Wong HN, Song B et al. The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. J Clin Invest 2005; 115 (2): 268–281. doi: 10.1172/JCI21848.

50. Carrasco DR, Sukhdeo K, Protopopova M et al. The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis. Cancer Cell 2007; 11 (4): 349–360. doi: 10.1016/j.ccr.2007.02.015.

51. Obeng EA, Carlson LM, Gutman DM et al. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 2006; 107 (12): 4907–4916. doi: 10.1182/blood-2005-08-3531.

52. Hideshima T, Chauhan D, Richardson P et al. NF- -kappa B as a therapeutic target in multiple myeloma. J Biol Chem 2002; 277 (19): 16639–16647. doi: 10.1074/jbc.M200360200.

53. Zhang D, De Veirman K, Fan R et al. ER stress arm XBP1s plays a pivotal role in proteasome inhibition-induced bone formation. Stem Cell Res Ther 2020; 11 (1): 516. doi: 10.1186/s13287-020-02037-3.

54. Kumar SK, Callander NS, Alsina M et al. NCCN Guidelines Insights: Multiple Myeloma, Version 3.2018. J Natl Compr Canc Netw 2018; 16 (1): 11–20. doi: 10.6004/jnccn.2018.0002.

55. Carlsten M, Namazi A, Reger R et al. Bortezomib sensitizes multiple myeloma to NK cells via ER-stress--induced suppression of HLA-E and upregulation of DR5. Oncoimmunology 2019; 8 (2): e1534664. doi: 10.1080/2162402X.2018.1534664.

56. Haney SL, Varney ML, Williams JT et al. Geranylgeranyl diphosphate synthase inhibitor and proteasome inhibitor combination therapy in multiple myeloma. Exp Hematol Oncol 2022; 11 (1): 5. doi: 10.1186/s40164-022-00261-6.

57. Kikuchi S, Suzuki R, Ohguchi H et al. Class IIa HDAC inhibition enhances ER stress-mediated cell death in multiple myeloma. Leukemia 2015; 29 (9): 1918–1927. doi: 10.1038/leu.2015.83.

58. Kawaguchi T, Miyazawa K, Moriya S et al. Combined treatment with bortezomib plus bafilomycin A1 enhances the cytocidal effect and induces endoplasmic reticulum stress in U266 myeloma cells: crosstalk among proteasome, autophagy-lysosome and ER stress. Int J Oncol 2011; 38 (3): 643–654. doi: 10.3892/ijo.2010.882.

59. Moriya S, Komatsu S, Yamasaki K et al. Targeting the integrated networks of aggresome formation, proteasome, and autophagy potentiates ER stress‑mediated cell death in multiple myeloma cells. Int J Oncol 2015; 46 (2): 474–486. doi: 10.3892/ijo.2014.2773.

60. Mimura N, Hideshima T, Shimomura T et al. Selective and potent Akt inhibition triggers anti-myeloma activities and enhances fatal endoplasmic reticulum stress induced by proteasome inhibition. Cancer Res 2014; 74 (16): 4458–4469. doi: 10.1158/0008-5472.CAN-13-3652.

61. Meister S, Frey B, Lang VR et al. Calcium channel blocker verapamil enhances endoplasmic reticulum stress and cell death induced by proteasome inhibition in myeloma cells. Neoplasia 2010; 12 (7): 550–561. doi: 10.1593/neo.10228.

62. Shirazi F, Jones RJ, Singh RK et al. Activating KRAS, NRAS, and BRAF mutants enhance proteasome capacity and reduce endoplasmic reticulum stress in multiple myeloma. Proc Natl Acad Sci U S A 2020; 117 (33): 20004–20014. doi: 10.1073/pnas.2005052117.

63. Besse L, Besse A, Mendez-Lopez M et al. A metabolic switch in proteasome inhibitor-resistant multiple myeloma ensures higher mitochondrial metabolism, protein folding and sphingomyelin synthesis. Haematologica 2019; 104 (9): e415–e419. doi: 10.3324/haematol.2018.207704.

64. Flanagan K, Kumari R, Miettinen JJ et al. The peptide--drug conjugate melflufen modulates the unfolded protein response of multiple myeloma and amyloidogenic plasma cells and induces cell death. Hemasphere 2022; 6 (3): e687. doi: 10.1097/HS9.0000000000000687.