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miR-381 induces sensitivity of breast cancer cells to doxorubicin by inactivation of MAPK signaling via FYN.

Abstract
The emergence of drug resistance is still a daunting challenge for the effective therapy of cancer patients. miRNAs have been elucidated as an important regulator in chemoresistance of anti-cancer drugs. miR-381 is found to exert tumor-suppressive effect in breast cancer. However, its role in modulating the sensitivity of doxorubicin (DOX) remains unknown. In this study, we found that miR-381 expression was down-regulated in DOX-resistant breast cancer cells. miR-381 overexpression increased DOX sensitivity and enhanced DOX-induced apoptosis in breast cancer cells. Moreover, miR-381 could directly target FYN to suppress its expression. Additionally, FYN knockdown displayed similar effect on DOX sensitivity as miR-381 up-regulation. Furthermore, FYN overexpression partly reversed miR-381-induced sensitivity to DOX. Finally, enforced expression of miR-381 also improved DOX sensitivity of breast cancer cells in vivo. In summary, miR-381 inactivated MAPK signaling by down-regulating FYN, thereby promoting the chemosensitization of breast cancer cells to DOX. Therefore, miR-381/FYN/MAPK pathway may be applied as a novel target to overcome DOX resistance in breast cancer patients.
AuthorsHailong Mi, Xiaochun Wang, Fang Wang, Lin Li, Mingzhi Zhu, Nan Wang, Youyi Xiong, Yuanting Gu
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 839 Pg. 66-75 (Nov 15 2018) ISSN: 1879-0712 [Electronic] Netherlands
PMID30266665 (Publication Type: Journal Article)
CopyrightCopyright © 2018 Elsevier B.V. All rights reserved.
Chemical References
  • MIRN381 microRNA, human
  • MicroRNAs
  • Doxorubicin
  • Proto-Oncogene Proteins c-fyn
Topics
  • Animals
  • Apoptosis (drug effects, genetics)
  • Base Sequence
  • Breast Neoplasms (pathology)
  • Down-Regulation (drug effects, genetics)
  • Doxorubicin (pharmacology)
  • Drug Resistance, Neoplasm (drug effects, genetics)
  • Humans
  • MAP Kinase Signaling System (drug effects, genetics)
  • MCF-7 Cells
  • Male
  • Mice
  • MicroRNAs (genetics)
  • Proto-Oncogene Proteins c-fyn (genetics)
  • Xenograft Model Antitumor Assays

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