Abstract
Nucleolin (NCL, C23) is an important nucleocytoplasmic multifunctional protein. Due to its multifaceted profile and high expression in cancer, NCL is considered to be a marker of drug resistance associated with chemotherapy. However, the biochemical mechanisms in which NCL suppresses drug sensitivity in several cancers have yet to be fully elucidated. This study aims to explore the effect of NCL on drug sensitivity and its potential mechanism in CA46 Burkitt's lymphoma (BL) cells. CA46 BL cells were transfected with lentiviruses carrying the NCL gene (CA46‐NCL‐overexpression, CA46‐NCL‐OE), or shRNA sequences that target the endogenous NCL gene (CA46‐NCL‐knockdown, CA46‐NCL‐KD). Adriamycin (ADM) IC50 levels for CA46‐NCL‐overexpressed (OE), CA46‐NCL‐OE control (OEC), CA46‐NCL‐knockdown (KD), and CA46‐NCL‐KD control (KDC) cells were 0.68 ± 0.06 μg/ml, 0.68 ± 0.06 μg/ml, 0.68 ± 0.06 μg/ml, and 0.30 ± 0.04 μg/ml, respectively. Apoptosis rates were significantly increased following NCL KD, whereas the opposite effect was noted in OE cells. A significant reduction of B‐cell lymphoma 2 (Bcl‐2) mRNA and protein levels in KD cells was observed, while OE cells displayed the opposite effect. The stability of Bcl‐2 mRNA was influenced by NCL levels, the half‐life of which was extended after NCL‐OE, whereas it was reduced in KD cells. Finally, results of RNA‐immunoprecipitation assays indicated that NCL could bind to Bcl‐2 mRNA in CA46 cells. Taken together, these results suggested that NCL could mediate Bcl‐2 expression and stability, and thus enhance ADM resistance in CA46 BL cells.
Highlights
Burkitt’s lymphoma (BL) is a high‐grade, rapidly growing and aggressive B‐cell non‐Hodgkin’s lymphoma
We found that NCL OE can promote drug resistance in BL, a result which may be related to the stabilization of B‐cell lymphoma 2 (Bcl‐2) mRNA and decreased induction of apoptosis
It has been suggested that chemotherapeutic drug‐ induced apoptosis in HL‐60 cells is preceded by the Bcl‐2 mRNA destabilization and the downregulation of Bcl‐2 mRNA and protein levels (Bandyopadhyay, Sengupta, Fernandes, & Spicer, 2003; Riordan, Foroni, Hoffbrand, Mehta, & Wickremasinghe, 1998)
Summary
Burkitt’s lymphoma (BL) is a high‐grade, rapidly growing and aggressive B‐cell non‐Hodgkin’s lymphoma. Studies have clarified that Bcl‐2 protein overexpression results in an apoptosis inhibition effect, which subsequently leads to chemotherapy resistance in hematological tumors and other solid tumors (Pan et al, 2015; Ruefli‐ Brasse & Reed, 2017; Weller, Malipiero, Aguzzi, Reed, & Fontana, 1995). Recent studies have found NCL to be a Bcl‐2 mRNA stabilizing protein in HL‐60 leukemia cells (Otake, Sengupta, Bandyopadhyay, Spicer, & Fernandes, 2005). This protein binds to the ARE‐1 instability element in the 3′‐untranslated region (3′‐UTR) of the Bcl‐2 mRNA to protect it from ribonuclease degradation. We hypothesize that the regulation of Bcl‐2 mRNA stability by NCL may contribute to drug resistance in BL To address this hypothesis, we established NCL stable expressing cell models using lentivirus‐mediated. NCL overexpression (OE) or NCL knockdown (KD) in CA46 BL cells, and determined that Bcl‐2 (on a molecular level) likely involved in the contribution of NCL with respect to drug resistance
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