KMID : 0578320180410121008
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Molecules and Cells 2018 Volume.41 No. 12 p.1008 ~ p.1015
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Proteasome Inhibitor-Induced I¥êB/NF-¥êB Activation is Mediated by Nrf2-Dependent Light Chain 3B Induction in Lung Cancer Cells
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Lee Kyoung-Hee
Lee Jung-Sil Woo Ji-Su Lee Chang-Hoon Yoo Chul-Gyu
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Abstract
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I¥êB, a cytoplasmic inhibitor of nuclear factor-¥êB (NF-¥êB), 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¥êB¥á degradation via an alternative pathway, lysosome, which results in NF-¥êB 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¥êB¥á degradation is necessary. Here, we demonstrated that PI upregulates 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¥êB¥á 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¥êB¥á 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¥êB¥á 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¥êB/NF-¥êB pathway, which attenuates the anti-tumor efficacy of PIs.
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KEYWORD
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I¥êB, macroautophagy, Nrf2, nuclear factor-¥êB, proteasome inhibitor
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