Harmine inhibits breast cancer cell migration and invasion by inducing the degradation of Twist1.

Ebtesam Nafie,Elnaz Abdollahzadeh,Carlotta Glackin,Sandy Rodriguez,Junjun Liu,Jade Lolarga,Brandon Lam,Jonathan Guo,Rajeev Samant

doi:10.1371/journal.pone.0247652

Abstract

Breast cancer is the leading cause of cancer-related deaths in the United States. The majority of deaths (90%) in breast cancer patients is caused by invasion and metastasis–two features related to the epithelial-to-mesenchymal transition (EMT). Twist1 is a key transcription factor that promotes the EMT, which leads to cell migration, invasion, cancer metastasis, and therapeutic resistance. Harmine is a beta-carboline alkaloid found in a variety of plants and was recently shown to be able to induce degradation of Twist Family BHLH Transcription Factor 1 (Twist1) in non-small cell lung cancer cells (NSCLC). In this study, we show that harmine can inhibit migration and invasion of both human and mouse breast cancer cells in a dose-dependent manner. Further study shows that this inhibition is most likely achieved by inducing a proteasome-dependent Twist1 degradation. At the concentrations tested, harmine did not affect the viability of cells significantly, suggesting that its inhibition of cancer cell migration and invasion is largely independent of its cytotoxicity, but due to its ability to affect regulators of EMT such as Twist1. This result may facilitate the development of strategies that target Twist1 to treat metastatic breast cancer, as Twist1 is expressed at a high level in metastatic breast cancer cells but not in normal cells.

Highlights

In 2020, an estimated 276,480 new cases of invasive breast cancer are expected to be diagnosed in women in the U.S, along with 48,530 new cases of non-invasive breast cancer [1]
Mouse 4T1 (RRID: CVCL_0125) cells were provided by Dr Jing Yang at the University of California San Diego and cultured as described [20]. 4T1 twist-related protein (Twist)- cells stably express siRNA that knocks down the expression of endogenous Twist Family BHLH Transcription Factor 1 (Twist1), and 4T1 Twist+ stably express control siRNA that does not affect the expression of endogenous Twist1
There was no difference in migration between untreated BT549 Twist+ cell and the cells treated with dimethyl sulfoxide (DMSO)

Summary

Introduction

In 2020, an estimated 276,480 new cases of invasive breast cancer are expected to be diagnosed in women in the U.S, along with 48,530 new cases of non-invasive (in situ) breast cancer [1]. The majority of deaths from breast cancer are not due to the primary tumor itself, but are the result of metastasis to other parts of the body [2]. Metastasis is a process comprised of a series of sequential steps, starting with local invasion of surrounding tissues by cells originating from the primary tumor and continuing until tumor cells invade and intravasate into blood or lymphatic vessels [3, 4]. Harmine inhibits breast cancer cell migration and invasion. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Methods

Results

Conclusion