Research Article: Strictinin, a novel ROR1-inhibitor, represses triple negative breast cancer survival and migration via modulation of PI3K/AKT/GSK3ß activity

Date Published: May 31, 2019

Publisher: Public Library of Science

Author(s): Norman Fultang, Abhinav Illendula, Brian Chen, Chun Wu, Subash Jonnalagadda, Nathan Baird, Zachary Klase, Bela Peethambaran, Abdelilah Aboussekhra.

http://doi.org/10.1371/journal.pone.0217789

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 GSK3β. 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 GSK3ß’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 ROR1-targeting agents as therapeutic tools to reduce TNBC proliferation, survival and motility.

Partial Text

Approximately one in eight women are diagnosed with breast cancer each year. Of these new cases, 15–20% are Triple Negative [1]. Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer characterized by malignant cells void of hormone (Progesterone and Estrogen) receptors and Human Epidermal Growth Factor Receptor 2 (HER-2) [2]. The lack of these receptors, usually targeted by hormonal therapies like tamoxifen and fulvestrant, leads to an increased difficulty in treatment. Owing to its increased propensity for metastasis and invasion, TNBC prognosis and long-term survival is significantly worse than in other breast cancer subtypes [3]. In addition, traditional chemotherapeutics and radiation used in breast cancer therapy are often highly toxic to both TNBC cells and healthy cells. This leads to many negative and unwanted side effects, often causing a decrease in therapy adherence in patients. In recent years, there has thus been an increased effort to look for novel agents that can treat triple negative breast cancer or complement existing drugs, with minimal effects on non-malignant cells.

Current chemotherapeutic agents for TNBC, including taxanes and anthracyclines have been shown to be both hepatotoxic and cardiotoxic to patients [34,35] leading to disastrous side effects and a decrease in therapy adherence. The development of novel targeted anti-TNBC agents that can target TNBC with minimal effects on normal tissue is thus an especially vital mission in our efforts to treat the disease. Oncofetal receptors which are minimally expressed in normal adult tissue but overexpressed in most cancers are appealing candidates for the development of these targeted agents. One such receptor is the ROR1 receptor which is highly expressed in most human malignancies but only minimally in normal tissue [9]. ROR1 has emerged recently as a molecule of significant interest for the development of targeted small molecules, antibodies, chimeric antigen T-cells and other agents for cancer therapy [15–17]. In this study we describe the mode of action of strictinin, one such targeted agent, which inhibits the action of ROR1, repressing TNBC migration and survival via P13K/AKT/GSK3ß deregulation.

 

Source:

http://doi.org/10.1371/journal.pone.0217789

 

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