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The Long Non Coding RNA SAMMSON is a regulator of chemosensitivity and metabolic orientation in doxorubicin resistant breast cancer cells

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 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188404 | GEO | 2021/11/10

REPOSITORIES: GEO

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Project description:Recent studies have suggested that elevated expression of aldoketoreductase (AKR) 1C1 or 1C2 in tumour cells is associated with increased resistance to DNA damaging agents such as cisplatin and doxorubicin. However, it has not been shown whether selection of tumour cells for resistance to DNA-damaging anthracyclines actually results in increased expression of AKRs and increased conversion of anthracyclines to 10-fold less toxic 13-hydroxy metabolites. It is also unclear whether the induction of aldokeoreductases is temporally correlated with the onset of anthracycline resistance and whether there is a direct relationship between the level of AKR expression or activity and the magnitude of drug resistance. Through microarray profiling of MCF-7 breast cancer cells selected for progressive resistance to doxorubicin or epirubicin, we have identified several genes whose expression has been correlated with both the onset and magnitude of drug resistance, including a “1C” AKR. AKR 1C overexpression was verified by quantitative PCR. Also associated with the onset of anthracycline resistance were genes involved in drug transport (ABCB1), cell signaling and transcription (RDC1, CXCR4), cell proliferation or apoptosis (BMP7, CAV1), ROS protection (TXNRD1, MT2A), and structural or immune system proteins (IFI30, STMN1). Consistent with the role of AKRs in anthracycline resistance, doxorubicin- and epirubicin-resistant breast tumour cells exhibited 2.2-fold and 6.1-fold higher levels of the 13-hydroxy metabolite of doxorubicin (doxorubicinol) than wildtype MCF-7 cells. In addition, an inhibitor of AKR 1C2 (5- cholanic acid) almost completely restored sensitivity to doxorubicin in Abcb1-deficient doxorubicin-resistant cells, while having no effect on Abcb1-expressing epirubicin-resistant cells. Taken together, our findings strongly suggest the involvement of multiple genes in the acquisition of anthracycline resistance in breast tumor cells---in particular redox genes such as the 1C AKRs. Keywords: Drug resistance of breast cancer cells In order to identify genes whose expression strongly correlates with the acquisition or magnitude of drug resistance or are temporally related with the acquisition of resistance, we selected MCF-7 breast tumor cells for survival in increasing concentrations (doses) of doxorubicin or epirubicin. Panels of cells exhibiting progressive resistance to either doxorubicin (MCF-7DOX-2) or epirubicin (MCF-7EPI) were obtained. Cells were also “selected” in the absence of drug at each step during selection to serve as co-cultured control (MCF-7CC) cells. In this study, we have used cDNA microarray analysis of these cell lines to identify a variety of “redox” genes whose expression can be correlated with the acquisition or magnitude of drug resistance in MCF-7DOX-2 and MCF-7EPI cells, including a “1C” aldoketoreductase (AKR).