Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

Proteasome Inhibitor-Induced IκB/NF-κB Activation is Mediated by Nrf2-Dependent Light Chain 3B Induction in Lung Cancer Cells

  • Lee, Kyoung-Hee (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital) ;
  • Lee, Jungsil (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Woo, Jisu (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital) ;
  • Lee, Chang-Hoon (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital) ;
  • Yoo, Chul-Gyu (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital)
  • Received : 2018.06.28
  • Accepted : 2018.09.13
  • Published : 2018.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

$I{\kappa}B$, a cytoplasmic inhibitor of nuclear factor-${\kappa}B$ ($NF-{\kappa}B$), is reportedly degraded via the proteasome. However, we recently found that long-term incubation with proteasome inhibitors (PIs) such as PS-341 or MG132 induces $I{\kappa}B{\alpha}$ degradation via an alternative pathway, lysosome, which results in $NF-{\kappa}B$ activation and confers resistance to PI-induced lung cancer cell death. To enhance the anti-cancer efficacy of PIs, elucidation of the regulatory mechanism of PI-induced $I{\kappa}B{\alpha}$ degradation is necessary. Here, we demonstrated that PI up-regulates nuclear factor (erythroid-derived 2)-like 2 (Nrf2) via both de novo protein synthesis and Kelch-like ECH-associated protein 1 (KEAP1) degradation, which is responsible for $I{\kappa}B{\alpha}$ degradation via macroautophagy activation. PIs increased the protein level of light chain 3B (LC3B, macroautophagy marker), but not lysosome-associated membrane protein 2a (Lamp2a, the receptor for chaperone-mediated autophagy) in NCI-H157 and A549 lung cancer cells. Pretreatment with macroautophagy inhibitor or knock-down of LC3B blocked PI-induced $I{\kappa}B{\alpha}$ degradation. PIs up-regulated Nrf2 by increasing its transcription and mediating degradation of KEAP1 (cytoplasmic inhibitor of Nrf2). Overexpression of dominant-negative Nrf2, which lacks an N-terminal transactivating domain, or knock-down of Nrf2 suppressed PI-induced LC3B protein expression and subsequent $I{\kappa}B{\alpha}$ degradation. Thus, blocking of the Nrf2 pathway enhanced PI-induced cell death. These findings suggest that Nrf2-driven induction of LC3B plays an essential role in PI-induced activation of the $I{\kappa}B$/$NF-{\kappa}B$ pathway, which attenuates the anti-tumor efficacy of PIs.

Keywords

E1BJB7_2018_v41n12_1008_f0001.png 이미지

Fig. 1. PI activates IκB/NF-κB pathway.

E1BJB7_2018_v41n12_1008_f0002.png 이미지

Fig. 2. PI-induced IκBα degradation is associated with macroautophagy.

E1BJB7_2018_v41n12_1008_f0003.png 이미지

Fig. 3. Macroautophagy mediates PI-induced IκBα degradation.

E1BJB7_2018_v41n12_1008_f0004.png 이미지

Fig. 4. PI-induced IκBα degradation is mediated by Nrf2 up-regulation via both de novo protein synthesis and KEAP1 degradation.

E1BJB7_2018_v41n12_1008_f0005.png 이미지

Fig. 5. PI-induced Nrf2 activation suppresses PI-induced cell death.

References

  1. Aghajanian, C., Soignet, S., Dizon, D.S., Pien, C.S., Adams, J., Elliott, P.J., Sabbatini, P., Miller, V., Hensley, M.L., Pezzulli, S., et al. (2002). A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin. Cancer Res. 8, 2505-2511.
  2. Besse, B., Planchard, D., Veillard, A.S., Taillade, L., Khayat, D., Ducourtieux, M., Pignon, J.P., Lumbroso, J., Lafontaine, C., Mathiot, C., et al. (2012). Phase 2 study of frontline bortezomib in patients with advanced non-small cell lung cancer. Lung Cancer 76, 78-83. https://doi.org/10.1016/j.lungcan.2011.09.006
  3. Coux, O., Tanaka, K., and Goldberg, A.L. (1996). Structure and functions of the 20S and 26S proteasomes. Annu. Rev. Biochem. 65, 801-847. https://doi.org/10.1146/annurev.bi.65.070196.004101
  4. Cuervo, A.M. (2004). Autophagy: many paths to the same end. Mol. Cell. Biochem. 263, 55-72. https://doi.org/10.1023/B:MCBI.0000041848.57020.57
  5. Ding, Z.B., Hui, B., Shi, Y.H., Zhou, J., Peng, Y.F., Gu, C.Y., Yang, H., Shi, G.M., Ke, A.W., Wang, X.Y., et al. (2011). Autophagy activation in hepatocellular carcinoma contributes to the tolerance of oxaliplatin via reactive oxygen species modulation. Clin. Cancer Res. 17, 6229-6238. https://doi.org/10.1158/1078-0432.CCR-11-0816
  6. Dreger, H., Westphal, K., Weller, A., Baumann, G., Stangl, V., Meiners, S., and Stangl, K. (2009). Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for proteasome inhibitormediated cardioprotection. Cardiovasc. Res. 83, 354-361. https://doi.org/10.1093/cvr/cvp107
  7. Esclatine, A., Chaumorcel, M., and Codogno, P. (2009). Macroautophagy signaling and regulation. Curr. Top. Microbiol. Immunol. 335, 33-70.
  8. Fanucchi, M.P., Fossella, F.V., Belt, R., Natale, R., Fidias, P., Carbone, D.P., Govindan, R., Raez, L.E., Robert, F., Ribeiro, M., et al. (2006). Randomized phase II study of bortezomib alone and bortezomib in combination with docetaxel in previously treated advanced nonsmall-cell lung cancer. J. Clin. Oncol. 24, 5025-5033. https://doi.org/10.1200/JCO.2006.06.1853
  9. Gao, Z., Gammoh, N., Wong, P.M., Erdjument-Bromage, H., Tempst, P., and Jiang, X. (2010). Processing of autophagic protein LC3 by the 20S proteasome. Autophagy 6, 126-137. https://doi.org/10.4161/auto.6.1.10928
  10. Goldberg, A.L., Stein, R., and Adams, J. (1995). New insights into proteasome function: from archaebacteria to drug development. Chem. Biol. 2, 503-508. https://doi.org/10.1016/1074-5521(95)90182-5
  11. Hou, X., Bai, X., Gou, X., Zeng, H., Xia, C., Zhuang, W., Chen, X., Zhao, Z., Huang, M., Jin, J. (2015). 3',4',5',5,7-pentamethoxyflavone sensitizes Cisplatin-resistant A549 cells to Cisplatin by inhibition of Nrf2 pathway. Mol. Cells 38, 396-401. https://doi.org/10.14348/molcells.2015.2183
  12. Kim, J.Y., Lee, S., Hwangbo, B., Lee, C.T., Kim, Y.W., Han, S.K., Shim, Y.S., and Yoo, C.G. (2000). NF-kappaB activation is related to the resistance of lung cancer cells to TNF-alpha-induced apoptosis. Biochem. Biophys. Res. Commun. 273, 140-146. https://doi.org/10.1006/bbrc.2000.2909
  13. Kobayashi, A., Kang, M.I., Watai, Y., Tong, K.I., Shibata, T., Uchida, K., and Yamamoto, M. (2006). Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol. Cell Biol. 26, 221-229. https://doi.org/10.1128/MCB.26.1.221-229.2006
  14. Lee, K.H., Jeong, J., and Yoo, C.G. (2013). Long-term incubation with proteasome inhibitors (PIs) induces IkappaBalpha degradation via the lysosomal pathway in an IkappaB kinase (IKK)-dependent and IKK-independent manner. J. Biol. Chem. 288, 32777-32786. https://doi.org/10.1074/jbc.M113.480921
  15. Leinonen, H.M., Kansanen, E., Polonen, P., Heinaniemi, M., and Levonen, A.L. (2014). Role of the Keap1-Nrf2 pathway in cancer. Adv. Cancer Res. 122, 281-320.
  16. Li, J., Hou, N., Faried, A., Tsutsumi, S., and Kuwano, H. (2010). Inhibition of autophagy augments 5-fluorouracil chemotherapy in human colon cancer in vitro and in vivo model. Eur. J. Cancer 46, 1900-1909. https://doi.org/10.1016/j.ejca.2010.02.021
  17. Lim, J., Lee, S.H., Cho, S., Lee, I.S., Kang, B.Y., and Choi, H.J. (2013). 4-methoxychalcone enhances cisplatin-induced oxidative stress and cytotoxicity by inhibiting the Nrf2/ARE-mediated defense mechanism in A549 lung cancer cells. Mol. Cells 36, 340-346. https://doi.org/10.1007/s10059-013-0123-9
  18. Ling, Y.H., Liebes, L., Zou, Y., and Perez-Soler, R. (2003). Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells. J. Biol. Chem. 278, 33714-33723. https://doi.org/10.1074/jbc.M302559200
  19. Majeski A.E., and Dice, J.F. (2004). Mechanisms of chaperonemediated autophagy. Int. J. Biochem. Cell Biol. 36, 2435-2444. https://doi.org/10.1016/j.biocel.2004.02.013
  20. Maki, C.G., Huibregtse, J.M., and Howley, P.M. (1996). In vivo ubiquitination and proteasome-mediated degradation of p53(1). Cancer Res. 56, 2649-2654.
  21. Mandrekar, S.J., Schild, S.E., Hillman, S.L., Allen, K.L., Marks, R.S., Mailliard, J.A., Krook, J.E., Maksymiuk, A.W., Chansky, K., Kelly, K., et al. (2006). A prognostic model for advanced stage nonsmall cell lung cancer. Pooled analysis of North Central Cancer Treatment Group trials. Cancer 107, 781-792. https://doi.org/10.1002/cncr.22049
  22. Masdehors, P., Omura, S., Merle-Béral, H., Mentz, F., Cosset, J.M., Dumont, J., Magdelénat, H., and Delic, J. (1999). Increased sensitivity of CLL-derived lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin. Br. J. Haematol. 105, 752-757. https://doi.org/10.1046/j.1365-2141.1999.01388.x
  23. Moriya, S., Che, X.F., Komatsu, S., Abe, A., Kawaguchi, T., Gotoh, A., Inazu, M., Tomoda, A., and Miyazawa, K. (2013). Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells. Int. J. Oncol. 42, 1541-1550. https://doi.org/10.3892/ijo.2013.1870
  24. Mujumdar, N., Mackenzie, T.N., Dudeja, V., Chugh, R., Antonoff, M.B., Borja-Cacho, D., Sangwan, V., Dawra, R., Vickers, S.M., and Saluja, A.K. (2010). Triptolide induces cell death in pancreatic cancer cells by apoptotic and autophagic pathways. Gastroenterology 139, 598-608. https://doi.org/10.1053/j.gastro.2010.04.046
  25. Pagano, M., Tam, S.W., Theodoras, A.M., Beer-Romero, P., Del Sal, G., Chau, V., Yew, P.R., Draetta, G.F., and Rolfe, M. (1995). Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 269, 682-685. https://doi.org/10.1126/science.7624798
  26. Palombella, V.J., Rando, O.J., Goldberg, A.L., and Maniatis T. (1994). The ubiquitin-proteasome pathway is required for processing the NFkappa B1 precursor protein and the activation of NF-kappa B. Cell 78, 773-785. https://doi.org/10.1016/S0092-8674(94)90482-0
  27. Richardson, P.G., Barlogie, B., Berenson, J., Singhal, S., Jagannath, S., Irwin, D., Rajkumar, S.V., Srkalovic, G., Alsina, M., Alexanian, R., et al. (2003). A phase 2 study of bortezomib in relapsed, refractory myeloma. N. Engl. J. Med. 348, 2609-2617. https://doi.org/10.1056/NEJMoa030288
  28. Ryter, S.W., and Choi, A.M. (2015). Autophagy in lung disease pathogenesis and therapeutics. Redox. Biol. 4, 215-225. https://doi.org/10.1016/j.redox.2014.12.010
  29. Soligo, D., Servida, F., Delia, D., Fontanella, E., Lamorte, G., Caneva, L., Fumiatti, R., and Lambertenghi Deliliers, G. (2001). The apoptogenic response of human myeloid leukaemia cell lines and of normal and malignant haematopoietic progenitor cells to the proteasome inhibitor PSI. Br. J. Haematol. 113, 126-135. https://doi.org/10.1046/j.1365-2141.2001.02683.x
  30. van der Wijst, M.G., Huisman, C., Mposhi, A., Roelfes, G., and Rots, M.G. (2015). Targeting Nrf2 in healthy and malignant ovarian epithelial cells: Protection versus promotion. Mol. Oncol. 9, 1259-1273. https://doi.org/10.1016/j.molonc.2015.03.003
  31. Wu, W., Li, W., Zhou, Y., and Zhang, C. (2014). Inhibition of beclin1 affects the chemotherapeutic sensitivity of osteosarcoma. Int. J. Clin. Exp. Pathol. 7, 7114-7122.
  32. Yang, H., Wang, W., Zhang, Y., Zhao, J., Lin, E., Gao, J., and He, J. (2011). The role of NF-E2-related factor 2 in predicting chemoresistance and prognosis in advanced non-small-cell lung cancer. Clin. Lung Cancer 12, 166-171. https://doi.org/10.1016/j.cllc.2011.03.012
  33. Yang, Y., Ikezoe, T., Saito, T., Kobayashi, M., Koeffler, H.P., and Taguchi, H. (2004). Proteasome inhibitor PS-341 induces growth arrest and apoptosis of non-small cell lung cancer cells via the JNK/c-Jun/AP-1 signaling. Cancer Sci. 95, 176-180. https://doi.org/10.1111/j.1349-7006.2004.tb03200.x
  34. Zhou, Z.W., Li, X.X., He, Z.X., Pan, S.T., Yang, Y., Zhang, X., Chow, K., Yang, T., Qiu, J.X., Zhou, Q., et al. (2015). Induction of apoptosis and autophagy via sirtuin1- and PI3K/Akt/mTOR-mediated pathways by plumbagin in human prostate cancer cells. Drug Des. Devel. Ther. 9, 1511-1554.
  35. Zhu, L., Barret, E.C., Xu, Y., Liu, Z., Manoharan, A., and Chen, Y. (2013). Regulation of Cigarette Smoke(CS)-Induced Autophagy by Nrf2. PLoS One 8, e55695. https://doi.org/10.1371/journal.pone.0055695

Cited by

  1. Regulation of Proteasome Activity by (Post-)transcriptional Mechanisms vol.6, pp.None, 2018, https://doi.org/10.3389/fmolb.2019.00048