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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)
  • 투고 : 2018.06.28
  • 심사 : 2018.09.13
  • 발행 : 2018.12.31

초록

$I{\kappa}B$, 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.

키워드

$I{\kappa}B$;macroautophagy;Nrf2;nuclear factor-${\kappa}B$;proteasome inhibitor

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.

과제정보

연구 과제 주관 기관 : Seoul National University Hospital

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