A novel miR-34a target, protein kinase D1, stimulates cancer stemness and drug resistance through GSK3/beta-catenin signaling in breast canceropen access
- Authors
- Kim, Do Yeon; Park, Eun Young; Chang, EunSun; Kang, Hyeok-Gu; Koo, Yoonjin; Lee, Eun Ji; Ko, Je Yeong; Kong, Hyun Kyung; Chun, Kyung-Hee; Park, Jong Hoon
- Issue Date
- Mar-2016
- Publisher
- IMPACT JOURNALS LLC
- Keywords
- miR-34a; PRKD1; beta-catenin signaling; cancer stemness; drug resistance
- Citation
- ONCOTARGET, v.7, no.12, pp 14791 - 14802
- Pages
- 12
- Journal Title
- ONCOTARGET
- Volume
- 7
- Number
- 12
- Start Page
- 14791
- End Page
- 14802
- URI
- https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/9905
- DOI
- 10.18632/oncotarget.7443
- ISSN
- 1949-2553
1949-2553
- 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/PKC mu, leading to suppression of breast cancer stemness through GSK3/beta-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.
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