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Protein kinase CK2 activates Nrf2 via autophagic degradation of Keap1 and activation of AMPK in human cancer cells.

ABSTRACT: Protein kinase CK2 downregulation induces premature senescence in various human cell types via activation of the reactive oxygen species (ROS)-p53-p21Cip1/WAF1 pathway. The transcription factor "nuclear factor erythroid 2-related factor 2" (Nrf2) plays an important role in maintaining intracellular redox homeostasis. In this study, Nrf2 overexpression attenuated CK2 downregulation- induced ROS production and senescence markers including SA-?-gal staining and activation of p53-p21Cip1/WAF1 in human breast (MCF-7) and colon (HCT116) cancer cells. CK2 downregulation reduced the transcription of Nrf2 target genes, such as glutathione S-transferase, glutathione peroxidase 2, and glutathione reductase 1. Furthermore, CK2 downregulation destabilized Nrf2 protein via inhibiting autophagic degradation of Kelch-like ECHassociated protein 1 (Keap1). Finally, CK2 downregulation decreased the nuclear import of Nrf2 by deactivating AMP-activated protein kinase (AMPK). Collectively, our data suggest that both Keap1 stabilization and AMPK inactivation are associated with decreased activity of Nrf2 in CK2 downregulation-induced cellular senescence. [BMB Reports 2020; 53(5): 272-277].

SUBMITTER: Jang DE

PROVIDER: S-EPMC7262510 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Protein kinase CK2 activates Nrf2 via autophagic degradation of Keap1 and activation of AMPK in human cancer cells.

Jang Da Eun DE Song Junbin J Park Jeong-Woo JW Yoon Soo-Hyun SH Bae Young-Seuk YS

BMB reports 20200501 5

Protein kinase CK2 downregulation induces premature senescence in various human cell types via activation of the reactive oxygen species (ROS)-p53-p21<sup>Cip1/WAF1</sup> pathway. The transcription factor "nuclear factor erythroid 2-related factor 2" (Nrf2) plays an important role in maintaining intracellular redox homeostasis. In this study, Nrf2 overexpression attenuated CK2 downregulation- induced ROS production and senescence markers including SA-β-gal staining and activation of p53-p21<sup> ...[more]

PMID: 32317087

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Project description:Lipotoxicity, induced by saturated fatty acid (SFA)-mediated cell death, plays an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The KEAP1 (kelch like ECH associated protein 1)-NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2) pathway is a pivotal defense mechanism against lipotoxicity. We previously reported that SQSTM1/p62 has a cytoprotective role against lipotoxicity through activation of the noncanonical KEAP1- NFE2L2 pathway in hepatocytes. However, the underlying mechanisms and physiological relevance of this pathway have not been clearly defined. Here, we demonstrate that NFE2L2-mediated induction of SQSTM1 activates the noncanonical KEAP1-NFE2L2 pathway under lipotoxic conditions. Furthermore, we identified that SQSTM1 induces ULK1 (unc-51 like autophagy activating kinase 1) phosphorylation by facilitating the interaction between AMPK (AMP-activated protein kinase) and ULK1, leading to macroautophagy/autophagy induction, followed by KEAP1 degradation and NFE2L2 activation. Accordingly, the activity of this SQSTM1-mediated noncanonical KEAP1-NFE2L2 pathway conferred hepatoprotection against lipotoxicity in the livers of conventional sqstm1- and liver-specific sqstm1-knockout mice. Moreover, this pathway activity was evident in the livers of patients with nonalcoholic fatty liver. This axis could thus represent a novel target for NAFLD treatment. Abbreviations: ACACA: acetyl-CoA carboxylase alpha; ACTB: actin beta; BafA1: bafilomycin A1; CM-H2DCFDA:5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; CQ: chloroquine; CUL3: cullin 3; DMSO: dimethyl sulfoxide; FASN: fatty acid synthase; GSTA1: glutathione S-transferase A1; HA: hemagglutinin; Hepa1c1c7: mouse hepatoma cells; HMOX1/HO-1: heme oxygenase 1; KEAP1: kelch like ECH associated protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MTORC1: mechanistic target of rapamycin kinase complex 1; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NAC: N-acetyl-L-cysteine; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; NQO1: NAD(P)H quinone dehydrogenase 1; PA: palmitic acid; PARP: poly (ADP-ribose) polymerase 1; PRKAA1/2: protein kinase AMP-activated catalytic subunits alpha1/2; RBX1: ring-box 1; ROS: reactive oxygen species; SESN2: sestrin 2; SFA: saturated fatty acid; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1; TBK1: TANK binding kinase 1; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; ULK1: unc-51 like autophagy activating kinase.

Project description:BackgroundGlutathione S-transferase zeta 1 (GSTZ1) is the penultimate enzyme in phenylalanine/tyrosine catabolism. GSTZ1 is dysregulated in cancers; however, its role in tumorigenesis and progression of hepatocellular carcinoma (HCC) is largely unknown. We aimed to assess the role of GSTZ1 in HCC and to reveal the underlying mechanisms, which may contribute to finding a potential therapeutic strategy against HCC.MethodsWe first analyzed GSTZ1 expression levels in paired human HCC and adjacent normal tissue specimens and the prognostic effect of GSTZ1 on HCC patients. Thereafter, we evaluated the role of GSTZ1 in aerobic glycolysis in HCC cells on the basis of the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Furthermore, we assessed the effect of GSTZ1 on HCC proliferation, glutathione (GSH) concentration, levels of reactive oxygen species (ROS), and nuclear factor erythroid 2-related factor 2 (NRF2) signaling via gain- and loss- of GSTZ1 function in vitro. Moreover, we investigated the effect of GSTZ1 on diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) induced hepatocarcinogenesis in a mouse model of HCC.ResultsGSTZ1 was downregulated in HCC, thus indicating a poor prognosis. GSTZ1 deficiency significantly promoted hepatoma cell proliferation and aerobic glycolysis in HCC cells. Moreover, loss of GSTZ1 function depleted GSH, increased ROS levels, and enhanced lipid peroxidation, thus activating the NRF2-mediated antioxidant pathway. Furthermore, Gstz1 knockout in mice promoted DEN/CCl4-induced hepatocarcinogenesis via activation of the NRF2 signaling pathway. Furthermore, the antioxidant agent N-acetylcysteine and NRF2 inhibitor brusatol effectively suppressed the growth of Gstz1-knockout HepG2 cells and HCC progression in Gstz1-/- mice.ConclusionsGSTZ1 serves as a tumor suppressor in HCC. GSH depletion caused by GSTZ1 deficiency elevates oxidative stress, thus constitutively activating the NRF2 antioxidant response pathway and accelerating HCC progression. Targeting the NRF2 signaling pathway may be a promising therapeutic approach for this subset of HCC.

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Protein kinase CK2 activates Nrf2 via autophagic degradation of Keap1 and activation of AMPK in human cancer cells.

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Protein kinase CK2 activates Nrf2 via autophagic degradation of Keap1 and activation of AMPK in human cancer cells.

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