Lipid Droplet Biosynthesis Impairment through DGAT2 Inhibition Sensitizes MCF7 Breast Cancer Cells to Radiation.

Clelia Nisticò,Maria Mesuraca,Joana Fernandes Guerreiro,Geraldine Genard,Heather Mandy Bond,Maria Grazia Marafioti,Maria Francesca Spadea,Emanuela Chiarella,Joao Carlos Seco,Daniel Garcia-Calderón,Ilenia Aversa,Francesca Pagliari,Rachel Hanley,Luca Tirinato

doi:10.3390/ijms221810102

Abstract

Breast cancer is the most frequent cancer in women worldwide and late diagnosis often adversely affects the prognosis of the disease. Radiotherapy is commonly used to treat breast cancer, reducing the risk of recurrence after surgery. However, the eradication of radioresistant cancer cells, including cancer stem cells, remains the main challenge of radiotherapy. Recently, lipid droplets (LDs) have been proposed as functional markers of cancer stem cells, also being involved in increased cell tumorigenicity. LD biogenesis is a multistep process requiring various enzymes, including Diacylglycerol acyltransferase 2 (DGAT2). In this context, we evaluated the effect of PF-06424439, a selective DGAT2 inhibitor, on MCF7 breast cancer cells exposed to X-rays. Our results demonstrated that 72 h of PF-06424439 treatment reduced LD content and inhibited cell migration, without affecting cell proliferation. Interestingly, PF-06424439 pre-treatment followed by radiation was able to enhance radiosensitivity of MCF7 cells. In addition, the combined treatment negatively interfered with lipid metabolism-related genes, as well as with EMT gene expression, and modulated the expression of typical markers associated with the CSC-like phenotype. These findings suggest that PF-06424439 pre-treatment coupled to X-ray exposure might potentiate breast cancer cell radiosensitivity and potentially improve the radiotherapy effectiveness.

Highlights

IntroductionBreast cancer represents the most common cancer in women with an incidence of
In the light of the above, by interfering with lipid droplets (LDs) biosynthesis, we investigated the effects of a Diacylglycerol acyltransferase 2 (DGAT2) inhibitor (PF-06424439) [28,29] in X-ray-irradiated MCF7 breast cancer cells in order to potentially affect breast cancer cell radioresistance
MCF7 treatment with 10 μM of PF-06424439 for 72 h was chosen for the following experiments, as it did not significantly exhibit cytotoxic effects on the cells (Figure 1C)

Summary

Introduction

Breast cancer represents the most common cancer in women with an incidence of. Screening, early diagnosis, and targeted treatments represent the main strategies for improving breast cancer survival rates. Radiotherapy (RT) is one of the main approaches for breast cancer treatment and it can be used alone or in combination with other treatments such as surgery, chemotherapy, and immunotherapy. It has been shown that radiation, in combination with surgery, allows for a better tumor control and increases patients’ survival more efficiently in the early stage of the disease [2]. RT works by causing damages to cellular organelles and producing direct and indirect DNA single-strand breaks (SSBs) and/or double strand breaks (DSBs). DSBs, the most critical and difficult type of DNA damages to be repaired, are labelled by phosphorylation of histone

Methods

Results

Discussion

Conclusion