Prolyl isomerase Pin1 regulates doxorubicin-inducible P-glycoprotein level by reducing Foxo3 stability

Taiki Shimizu; Yoshimasa Bamba; Yosuke Kawabe; Tomokazu Fukuda; Fumihiro Fujimori; Katsuhiko Takahashi; Chiyoko Uchida; Takafumi Uchida

doi:10.1016/j.bbrc.2016.02.014

Prolyl isomerase Pin1 regulates doxorubicin-inducible P-glycoprotein level by reducing Foxo3 stability

Biochem Biophys Res Commun. 2016 Mar 4;471(2):328-33. doi: 10.1016/j.bbrc.2016.02.014. Epub 2016 Feb 10.

Authors

Taiki Shimizu¹, Yoshimasa Bamba¹, Yosuke Kawabe¹, Tomokazu Fukuda², Fumihiro Fujimori³, Katsuhiko Takahashi⁴, Chiyoko Uchida⁵, Takafumi Uchida⁶

Affiliations

¹ Molecular Enzymology, Department of Molecular Cell Science, Graduate School of Agricultural Science, Tohoku University, 1-1 Amamiya, Tsutsumidori, Aoba, Sendai, Miyagi, 981-8555 Japan.
² Animal Production Science, Tohoku University, Japan.
³ Biological Science and Technology, Tokyo Kasei University, Kaga 1-18-1, Itabashi, Tokyo 173-8062, Japan.
⁴ Institute of Medicinal Chemistry, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan.
⁵ Department of Human Development and Culture, Fukushima University, Kanayagawa 1, Fukushima, Fukushima 960-1296, Japan.
⁶ Molecular Enzymology, Department of Molecular Cell Science, Graduate School of Agricultural Science, Tohoku University, 1-1 Amamiya, Tsutsumidori, Aoba, Sendai, Miyagi, 981-8555 Japan. Electronic address: uchidat@biochem.tohoku.ac.jp.

PMID: 26874277
DOI: 10.1016/j.bbrc.2016.02.014

Abstract

It has been known that the phosphoSer/Thr-Pro-specific peptidyl prolyl cis/trans isomerase Pin1 regulates a variety of intracellular signaling pathways, including the response to the genotoxic drug doxorubicin. Pin1 binds phosphorylated p53 and stabilizes p53 to cause cell cycle arrest and apoptosis quickly in response to doxorubicin. Here we show another mechanism of Pin1 to maintain cell sensitivity to genotoxic stress, irrespective of whether p53 is present or not. In response to the genotoxic drug, Pin1 binds and decreases levels of the phosphorylated Foxo3, the positive transcription factor of P-glycoprotein (P-gp) gene. Through this mechanism of action, Pin1 decreases the level of P-gp and signals the cell to pump the genotoxic drugs out. This shows that Pin1 is implemented in maintaining the susceptibility to the genotoxic drugs by controlling P-gp level as well as p53-dependent apoptosis and cell cycle signaling pathways.

Keywords: Doxorubicin; Foxo3; P-glycoprotein; Pin1; p53.

Publication types

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

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
Antibiotics, Antineoplastic / administration & dosage
Dose-Response Relationship, Drug
Doxorubicin / administration & dosage*
Forkhead Box Protein O3
Forkhead Transcription Factors / metabolism*
Gene Expression Regulation, Neoplastic / drug effects
Humans
MCF-7 Cells
NIMA-Interacting Peptidylprolyl Isomerase
Peptidylprolyl Isomerase / metabolism*
Tumor Suppressor Protein p53 / metabolism*

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Antibiotics, Antineoplastic
FOXO3 protein, human
Forkhead Box Protein O3
Forkhead Transcription Factors
NIMA-Interacting Peptidylprolyl Isomerase
Tumor Suppressor Protein p53
Doxorubicin
PIN1 protein, human
Peptidylprolyl Isomerase