Journal article
Strictinin, a novel ROR1-inhibitor, represses triple negative breast cancer survival and migration via modulation of PI3K/AKT/GSK3 beta activity
PloS one, v 14(5), 0217789
31 May 2019
PMID: 31150511
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Triple Negative Breast Cancer (TNBC), the most aggressive subtype of breast cancer, is characterized by the absence of hormone receptors usually targeted by hormone therapies like Tamoxifen. Because therapy success and survival rates for TNBC lag far behind other breast cancer subtypes, there is significant interest in developing novel anti-TNBC agents that can target TNBC specifically, with minimal effects on non-malignant tissue. To this aim, our study describes the anti-TNBC effect of strictinin, an ellagitanin previously isolated from Myrothamnus flabellifolius. Using various in silico and molecular techniques, we characterized the mechanism of action of strictinin in TNBC. Our results suggest strictinin interacts strongly with Receptor Tyrosine Kinase Orphan like 1 (ROR1). ROR1 is an oncofetal receptor highly expressed during development but not in normal adult tissue. It is highly expressed in several human malignancies however, owing to its numerous pro-tumor functions. Via its interaction and inhibition of ROR1, strictinin reduced AKT phosphorylation on ser-473, inhibiting downstream phosphorylation and inhibition of GSK3 beta. The reduction in AKT phosphorylation also correlated with decreased cell survival and activation of the caspase-mediated intrinsic apoptotic cascade. Strictinin treatment also repressed cell migration and invasion in a beta-catenin independent manner, presumably via the reactivated GSK3 beta's repressing effect on microtubule polymerization and focal adhesion turnover. This could be of potential therapeutic interest considering heightened interest in ROR1 and other receptor tyrosine kinases as targets for development of anti-cancer agents. Further studies are needed to validate these findings in other ROR1-expressing malignancies but also in more systemic models of TNBC. Our findings do however underline the potential of strictinin and other ROR1targeting agents as therapeutic tools to reduce TNBC proliferation, survival and motility.
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Details
- Title
- Strictinin, a novel ROR1-inhibitor, represses triple negative breast cancer survival and migration via modulation of PI3K/AKT/GSK3 beta activity
- Creators
- Norman Fultang - University of the SciencesAbhinav Illendula - University of the SciencesBrian Chen - Rowan UniversityChun Wu - Rowan UniversitySubash Jonnalagadda - Rowan UniversityNathan Baird - University of the SciencesZachary Klase - University of the SciencesBela Peethambaran - University of the Sciences
- Publication Details
- PloS one, v 14(5), 0217789
- Publisher
- Public Library Science
- Number of pages
- 15
- Grant note
- Milton Lev Faculty Research Fund - University of the Sciences University of the Sciences
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000469759100110
- Scopus ID
- 2-s2.0-85066609172
- Other Identifier
- 991021902504404721
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- Web of Science research areas
- Biochemistry & Molecular Biology