PF-4708671, a specific inhibitor of p70 ribosomal S6 kinase 1, activates Nrf2 by promoting p62-dependent autophagic degradation of Keap1

Jeong Su Park; Dong Hoon Kang; Da Hyun Lee; Soo Han Bae

doi:10.1016/j.bbrc.2015.09.059

PF-4708671, a specific inhibitor of p70 ribosomal S6 kinase 1, activates Nrf2 by promoting p62-dependent autophagic degradation of Keap1

Biochem Biophys Res Commun. 2015 Oct 23;466(3):499-504. doi: 10.1016/j.bbrc.2015.09.059. Epub 2015 Sep 14.

Authors

Jeong Su Park¹, Dong Hoon Kang², Da Hyun Lee¹, Soo Han Bae³

Affiliations

¹ Severance Biomedical Science Institute, Republic of Korea; Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea.
² Department of Life Science and Ewha Research Center for Systems Biology, Republic of Korea; The Research Center for Cell Homeostasis, Ewha Womans University, Seoul 127-750, Republic of Korea.
³ Severance Biomedical Science Institute, Republic of Korea; Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea. Electronic address: [email protected].

PMID: 26381178
DOI: 10.1016/j.bbrc.2015.09.059

Abstract

p70 ribosomal S6 kinase 1 (S6K1) is an important serine/threonine kinase and downstream target of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. PF-4708671 is a specific inhibitor of S6K1, and prevents S6K1-mediated phosphorylation of the S6 protein. PF-4708671 treatment often leads to apoptotic cell death. However, the protective mechanism against PF-4708671-induced cell death has not been elucidated. The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is essential for protecting cells against oxidative stress. p62, an adaptor protein in the autophagic process, enhances Nrf2 activation through the impairment of Keap1 activity. In this study, we showed that PF-4708671 induces autophagic Keap1 degradation-mediated Nrf2 activation in p62-dependent manner. Furthermore, p62-dependent Nrf2 activation plays a crucial role in protecting cells from PF-4708671-mediated apoptosis.

Keywords: Autophagy; Kelch-like ECH-associated protein 1 (Keap1); Nuclear factor erythroid 2-related factor 2 (Nrf2); PF-4708671; p62; p70 ribosomal S6 kinase 1 (S6K1).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / deficiency
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Apoptosis / drug effects
Apoptosis / physiology
Autophagy / drug effects
Autophagy / physiology
Cells, Cultured
Cytoskeletal Proteins / genetics
Cytoskeletal Proteins / metabolism*
HeLa Cells
Heat-Shock Proteins / deficiency
Heat-Shock Proteins / genetics
Heat-Shock Proteins / metabolism*
Humans
Imidazoles / pharmacology*
Kelch-Like ECH-Associated Protein 1
Mice
NF-E2-Related Factor 2 / metabolism*
Piperazines / pharmacology*
Protein Kinase Inhibitors / pharmacology
Proteolysis / drug effects
RNA, Messenger / genetics
RNA, Messenger / metabolism
Reactive Oxygen Species / metabolism
Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors*
Sequestosome-1 Protein
Signal Transduction / drug effects

Substances

Adaptor Proteins, Signal Transducing
Cytoskeletal Proteins
Heat-Shock Proteins
Imidazoles
Keap1 protein, mouse
Kelch-Like ECH-Associated Protein 1
NF-E2-Related Factor 2
Nfe2l2 protein, mouse
PF-4708671
Piperazines
Protein Kinase Inhibitors
RNA, Messenger
Reactive Oxygen Species
Sequestosome-1 Protein
Sqstm1 protein, mouse
Ribosomal Protein S6 Kinases, 90-kDa
Rps6ka1 protein, mouse