CHIP regulates AKT/FoxO/Bim signaling in MCF7 and MCF10A cells

Yanrong Lv; Shanshan Song; Kai Zhang; Haidong Gao; Rong Ma

doi:10.1371/journal.pone.0083312

CHIP regulates AKT/FoxO/Bim signaling in MCF7 and MCF10A cells

PLoS One. 2013 Dec 20;8(12):e83312. doi: 10.1371/journal.pone.0083312. eCollection 2013.

Authors

Yanrong Lv¹, Shanshan Song², Kai Zhang¹, Haidong Gao¹, Rong Ma¹

Affiliations

¹ Department of Breast Surgery, QiLu Hospital of Shandong University, Jinan, Shandong, China.
² Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California, United States of America.

Abstract

A number of studies have shown that apoptosis resistance can be observed in multiple human tumors; however the detailed mechanism remains unclear. In the present study, we demonstrated that the abnormal overexpression of the C terminus of Hsc70-interacting protein (CHIP) induced apoptosis resistance by regulating the AKT/FoxO/Bim signaling pathway in the breast cancer cell MCF7 and the human non-tumorigenic cell MCF10A. We found that CHIP overexpression in MCF7 and MCF10A cells activated AKT and inhibited the Forkhead box O (FoxO) transcription factors FoxO1, FoxO3, and FoxO4, thereby inhibiting transcription of the target genes bim and pten. Inhibition of PI3K by a chemical reagent revealed that these events may be critical for CHIP-induced apoptosis resistance. We also determined that inhibition of FoxO3 by CHIP led to the decrease in PTEN and further activated the AKT survival pathway. We corroborated our findings in breast cancer tissues. In general, the CHIP-modulated AKT/FoxO/Bim signaling pathway was shown to induce apoptosis resistance by decreasing the protein level of the tumor suppressor PTEN in both transcriptional and post-translational regulations.

Publication types

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

MeSH terms

Apoptosis
Apoptosis Regulatory Proteins / genetics*
Apoptosis Regulatory Proteins / metabolism
Bcl-2-Like Protein 11
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Survival
Female
Forkhead Box Protein O1
Forkhead Transcription Factors / genetics*
Forkhead Transcription Factors / metabolism
Gene Expression Regulation, Neoplastic*
Humans
Membrane Proteins / genetics*
Membrane Proteins / metabolism
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / metabolism
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism
Protein Isoforms / genetics
Protein Isoforms / metabolism
Proto-Oncogene Proteins / genetics*
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-akt / genetics*
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction
Transcription, Genetic
Ubiquitin-Protein Ligases / genetics*
Ubiquitin-Protein Ligases / metabolism

Substances

Apoptosis Regulatory Proteins
BCL2L11 protein, human
Bcl-2-Like Protein 11
FOXO1 protein, human
Forkhead Box Protein O1
Forkhead Transcription Factors
Membrane Proteins
Protein Isoforms
Proto-Oncogene Proteins
STUB1 protein, human
Ubiquitin-Protein Ligases
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
PTEN Phosphohydrolase
PTEN protein, human

Grants and funding

The source of funding that has supported this work is the Nature Science of Shandong Province, Q2008C08 (http://www.sdnsf.gov.cn/portal/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.