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학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
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연구자들이 자신의 연구와 전문성을 널리 알리고, 새로운 협력의 기회를 만들 수 있는 네트워킹 공간이에요.
논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2018.12
- 수록면
- 1,008 - 1,015 (8page)
- DOI
- 10.14348/molcells.2018.0277
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초록· 키워드
오류제보하기
IκB, a cytoplasmic inhibitor of nuclear factor-κB (NF-κB), 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 IκBα degradation via an alternative pathway, lysosome, which results in NF-κB 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 IκBα 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 IκBα 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 PIinduced IκBα degradation. PIs up-regulated Nrf2 by increasing its transcription and mediating degradation of KEAP1 (cytoplasmic inhibitor of Nrf2). Overexpression of dominantnegative Nrf2, which lacks an N-terminal transactivating domain, or knock-down of Nrf2 suppressed PI-induced LC3B protein expression and subsequent IκBα 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 IκB/NF-κB pathway, which attenuates the anti-tumor efficacy of PIs.
목차
등록된 정보가 없습니다.
참고문헌 (35)
참고문헌 신청
Aghajanian, C. / 2002 / A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies / Clin. Cancer Res 8:2505~2511
Besse, B. / 2012 / Phase 2 study of frontline bortezomib in patients with advanced non-small cell lung cancer / Lung Cancer 76:78~83
Coux, O. / 1996 / Structure and functions of the 20S and 26S proteasomes / Annu. Rev. Biochem 65:801~847
Cuervo, A. M. / 2004 / Autophagy: many paths to the same end / Mol. Cell. Biochem 263:55~72
Ding, Z. B. / 2011 / Autophagy activation in hepatocellular carcinoma contributes to the tolerance of oxaliplatin via reactive oxygen species modulation / Clin. Cancer Res 17:6229~6238
Besse, B. / 2012 / Phase 2 study of frontline bortezomib in patients with advanced non-small cell lung cancer / Lung Cancer 76:78~83
Coux, O. / 1996 / Structure and functions of the 20S and 26S proteasomes / Annu. Rev. Biochem 65:801~847
Cuervo, A. M. / 2004 / Autophagy: many paths to the same end / Mol. Cell. Biochem 263:55~72
Ding, Z. B. / 2011 / Autophagy activation in hepatocellular carcinoma contributes to the tolerance of oxaliplatin via reactive oxygen species modulation / Clin. Cancer Res 17:6229~6238
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