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A novel miR-34a target, protein kinase D1, stimulates cancer stemness and drug resistance through GSK3/β-catenin signaling in breast cancer.
- Source :
-
Oncotarget [Oncotarget] 2016 Mar 22; Vol. 7 (12), pp. 14791-802. - Publication Year :
- 2016
-
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/β-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.
- Subjects :
- Animals
Apoptosis
Biomarkers, Tumor genetics
Biomarkers, Tumor metabolism
Breast Neoplasms drug therapy
Breast Neoplasms metabolism
Cell Proliferation
Doxorubicin pharmacology
Female
Glycogen Synthase Kinase 3 genetics
Humans
Mice
Mice, Nude
Neoplastic Stem Cells drug effects
Neoplastic Stem Cells metabolism
Phosphorylation
Protein Kinase C genetics
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
beta Catenin genetics
Breast Neoplasms pathology
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Glycogen Synthase Kinase 3 metabolism
MicroRNAs genetics
Neoplastic Stem Cells pathology
Protein Kinase C metabolism
beta Catenin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 26895471
- Full Text :
- https://doi.org/10.18632/oncotarget.7443