The Long Non-Coding RNA SAMMSON Is a Regulator of Chemosensitivity and Metabolic Orientation in MCF-7 Doxorubicin-Resistant Breast Cancer Cells

SIMPLE SUMMARY: Breast cancer is the most common cancer in women, representing about one third of cancers in developed countries. Despite recent advances in diagnostic methods and increasingly early detection, breast cancer recurrence occurs in more than 20% of patients. Chemoresistance represents an important cause of this recurrence, but the mechanisms involved in this phenomenon, are still largely unknown. One feature of chemoresistant cancer cells is the reorientation of the energetic metabolism to sustain cell proliferation. Recently, long non-coding RNAs (lncRNAs) have emerged as important regulators of cellular metabolic orientation. In the present work, we gave special attention to the long non-coding RNA SAMMSON and addressed the role of this lncRNA in metabolic orientation and chemoresistance of doxorubicin-resistant breast cancer cells. The results shed light on the possible modulation of the SAMMSON expression as an innovative therapeutic approach to target chemoresistant cancer cells specifically. ABSTRACT: Despite improvements in therapeutic strategies for treating breast cancers, tumor relapse and chemoresistance remain major issues in patient outcomes. Indeed, cancer cells display a metabolic plasticity allowing a quick adaptation to the tumoral microenvironment and to cellular stresses induced by chemotherapy. Recently, long non-coding RNA molecules (lncRNAs) have emerged as important regulators of cellular metabolic orientation. In the present study, we addressed the role of the long non-coding RNA molecule (lncRNA) SAMMSON on the metabolic reprogramming and chemoresistance of MCF-7 breast cancer cells resistant to doxorubicin (MCF-7dox). Our results showed an overexpression of SAMMSON in MCF-7dox compared to doxorubicin-sensitive cells (MCF-7). Silencing of SAMMSON expression by siRNA in MCF-7dox cells resulted in a metabolic rewiring with improvement of oxidative metabolism, decreased mitochondrial ROS production, increased mitochondrial replication, transcription and translation and an attenuation of chemoresistance. These results highlight the role of SAMMSON in the metabolic adaptations leading to the development of chemoresistance in breast cancer cells. Thus, targeting SAMMSON expression levels represents a promising therapeutic route to circumvent doxorubicin resistance in breast cancers.