Ribosome Biogenesis Regulator 1 Homolog (RRS1) Promotes Cisplatin Resistance by Regulating AEG-1 Abundance in Breast Cancer Cells

Abstract

Many ribosomal proteins are highly expressed in tumors and are closely related to their diagnosis, prognosis and pathological characteristics. However, few studies are available on the correlation between ribosomal proteins and chemoresistance. RRS1 (human regulator of ribosome synthesis 1), a critical nuclear protein involved in ribosome biogenesis, also plays a key role in the genesis and development of breast cancer by protecting cancer cells from apoptosis. Given that apoptosis resistance is one of the causes of the cisplatin resistance of tumor cells, our aim was to determine the relationship between RRS1 and cisplatin resistance in breast cancer cells. Here, we report that RRS1 is associated with cisplatin resistance in breast cancer cells. RRS1 silencing increased the sensitivity of MCF-7/DDP cells to cisplatin and inhibited cancer cell proliferation by blocking cell cycle distribution and enhancing apoptosis. AEG-1 (astrocyte elevated gene-1) promotes drug resistance by interfering with the ubiquitination and proteasomal degradation of MDR1 (multidrug resistance gene 1), thereby enhancing drug efflux. We found that RRS1 binds to and stabilizes AEG-1 by inhibiting ubiquitination and subsequent proteasomal degradation, which then promotes drug efflux by upregulating MDR1. Furthermore, RRS1 also induces apoptosis resistance in breast cancer cells through the ERK/Bcl-2/BAX signaling pathway. Our study is the first to show that RRS1 sensitizes breast cancer cells to cisplatin by binding to AEG-1, and it provides a theoretical basis to improve the efficacy of cisplatin-based chemotherapy.

Regulator of Ribosome Synthesis 1 (RRS1) Stabilizes GRP78 and Promotes Breast Cancer Progression

“…Increased ribosome biogenesis is necessary to maintain the elevated proliferation rate of tumor cells [ 34 ]. Recent research has implicated RRS1 in the development of several malignancies and it is significantly upregulated in various tumors [ 35 , 36 , 37 , 38 ]. The results of our previous studies have demonstrated the function of RRS1 in the growth of BC cells.…”

“…The GV492-GFP and GV115-EGFP lentiviral expression system (Shanghai GeneChem Co., Ltd.) was utilized for the transfection of cells expressing shRNA targeting RRS1 (sh-RRS1), control shRNA (sh-CON), scrambled control (OE-CON), and overexpressed RRS1 (OE-RRS1). The cells were subjected to infection with the corresponding lentiviruses at a multiplicity of infection (MOI) of 20 [ 37 , 38 ]. When the cells reached 20% to 30% confluence, they were transfected with the virus and Hitrans A&P (Shanghai GeneChem Co., Ltd.).…”

Berberine: Potential preventive and therapeutic strategies for human colorectal cancer

“…126 GRP78 has been shown to play a key role in the mechanism of cancer growth. 127 GRP78, a crucial factor in the mechanism of cancer growth, is significantly downregulated by BBR in SW480 cells, leading to tumor inhibition and apoptosis. 128 Notably, reprogramming of lipid metabolism is a widely accepted hallmark of malignancy that affects the development of various tumors.…”