title: CHIP regulates AKT/FoxO/Bim signaling in MCF7 and MCF10A cells.
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.
authors.affiliation: Department of Breast Surgery, QiLu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Song
authors.affiliation: Department of Breast Surgery, QiLu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Breast Surgery, QiLu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Haidong
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Breast Surgery, QiLu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Ma
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human