A novel miR-34a target, protein kinase D1, stimulates cancer stemness and drug resistance through GSK3/ß-catenin signaling in breast cancer.
Oncotarget
; 7(12): 14791-802, 2016 Mar 22.
Article
in En
| MEDLINE
| ID: mdl-26895471
ABSTRACT
One of the properties of human breast cancer cells is cancer stemness, which is characterized by self-renewal capability and drug resistance. Protein kinase D1 (PRKD1) functions as a key regulator of many cellular processes and is downregulated in invasive breast cancer cells. In this study, we found that PRKD1 was upregulated in MCF-7-ADR human breast cancer cells characterized by drug resistance. Additionally, we discovered that PRKD1 expression was negatively regulated by miR-34a binding to the PRKD1 3'-UTR. PRKD1 expression increased following performance of a tumorsphere formation assay in MCF-7-ADR cells. We also found that reduction of PRKD1 by ectopic miR-34a expression or PRKD1 siRNA treatment resulted in suppressed self-renewal ability in breast cancer stem cells. Furthermore, we confirmed that the PRKD1 inhibitor CRT0066101 reduced phosphorylated PKD/PKCµ, leading to suppression of breast cancer stemness through GSK3/ß-catenin signaling. PRKD1 inhibition also influenced apoptosis initiation in MCF-7-ADR cells. Tumors from nude mice treated with miR-34a or CRT0066101 showed suppressed tumor growth, proliferation, and induced apoptosis. These results provide evidence that regulation of PRKD1, a novel miR-34a target, contributes to overcoming cancer stemness and drug resistance in human breast cancer.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Neoplastic Stem Cells
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Protein Kinase C
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Breast Neoplasms
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Gene Expression Regulation, Neoplastic
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Drug Resistance, Neoplasm
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Glycogen Synthase Kinase 3
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MicroRNAs
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Beta Catenin
Limits:
Animals
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Female
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Humans
Language:
En
Journal:
Oncotarget
Year:
2016
Document type:
Article
Publication country:
EEUU
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ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA