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PF-4708671, a Specific Inhibitor of p70 Ribosomal S6 Kinase 1, Activates Nrf2 by Promoting p62-dependent Autophagic Degradation of Keap1

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

Biochem Biophys Res Commun. 2015 Oct 23;466(3):499-504.

PMID: 26381178

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1255517760	PF-4708671		1255517-76-0	Price

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