| Protein kinase CK2 activates Nrf2 via autophagic degradation of Keap1 and activation of AMPK in human cancer cells |
Da eun Jang1,# (Graduate student), Junbin Song1,# (Graduate student), Jeong-Woo Park  1 (Graduate student), Soo-Hyun Yoon2 (Research worker), Young-Seuk Bae 1,* (Professor) |
| 1School of Life Sciences, BK21 Plus KNU Creative BioResearch Group and 2Research Institute of Pharmaceutical Sciences, Kyungpook National University |
|
Abstract
Protein kinase CK2 downregulation induces premature senescence in various human cell types via activation of the reactive oxygen species (ROS)–p53–p21 Cip1/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-モ-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 ECH-associated 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.
|
| Abstract, Accepted Manuscript(in press) [Submitted on February 25, 2020, Accepted on March 31, 2020] |
|