Nogo-B receptor promotes the chemoresistance of human hepatocellular carcinoma via the ubiquitination of p53 protein

Abstract

Nogo-B receptor (NgBR), a type I single transmembrane domain receptor is the specific receptor for Nogo-B. Our previous work demonstrated that NgBR is highly expressed in breast cancer cells, where it promotes epithelial mesenchymal transition (EMT), an important step in metastasis. Here, we show that both in vitro and in vivo increased expression of NgBR contributes to the increased chemoresistance of Bel7402/5FU cells, a stable 5-FU (5-Fluorouracil) resistant cell line related Bel7402 cells. NgBR knockdown abrogates S-phase arrest in Bel7402/5FU cells, which correlates with a reduction in G1/S phase checkpoint proteins p53 and p21. In addition, NgBR suppresses p53 protein levels through activation of the PI3K/Akt/MDM2 pathway, which promotes p53 degradation via the ubiquitin proteasome pathway and thus increases the resistance of human hepatocellular cancer cells to 5-FU. Furthermore, we found that NgBR expression is associated with a poor prognosis of human hepatocellular carcinoma (HCC) patients. These results suggest that targeting NgBR in combination with chemotherapeutic drugs, such as 5-FU, could improve the efficacy of current anticancer treatments.

Nogo‐B promotes tumor angiogenesis and provides a potential therapeutic target in hepatocellular carcinoma

“…Some preliminary studies of NgBR expression in tumor cells have also been performed recently, but the results differ for different tumor types. For instance, NgBR was upregulated in breast cancer compared with normal breast tissue and the expression of NgBR promoted the chemoresistance of HCC cells (Dong et al, 2016;Wang et al, 2013). In contrast, association studies demonstrated that the expression of NgBR was negatively correlated with the malignancy grade in invasive ductal breast carcinoma, non-small-cell lung carcinomas, and malignant melanoma (Calik et al, 2016;Pula et al, 2014a,b).…”

Nogo‑B receptor in relevant carcinoma: Current achievements, challenges and aims (Review)

“…More importantly, targeting this signalling axis has been revealed to be promising for the treatment of cancer. It has been predominantly reported to have an oncogenic function and elevated expression in certain cancer types, including invasive ductal breast carcinoma (IDC) (14), hepatocellular carcinoma (HCC) (15), malignant melanoma (MM) (16) and non-small cell lung carcinomas (NSCLC) (17), which implies that targeting this signalling axis may have potential for retarding or ameliorating cancer progression.…”

“…In summary, NgBR serves a notable role in a number of human diseases, particularly cancer, which is a highly studied and complex subject (3). Once the first report of its effect on breast cancer was published in 2013 (14), numerous studies on the function of NgBR in the mechanism of cancer have been reported, and NgBR has gradually become a novel research hotspot globally (14)(15)(16)(17). However, no systematic review of the latest research results for NgBR in the cancer research field has been published, to the best of our knowledge.…”

“…However, no systematic review of the latest research results for NgBR in the cancer research field has been published, to the best of our knowledge. The present review assesses and discusses novel advances achieved in previous studies on NgBR, with a particular emphasis on the expression and pathophysiological effects of NgBR on relevant human cancer types (17), including IDC (14), MM (16), HCC (15) and NSCLC (17). The present review additionally assessed the data implicating NgBR in the regulation of lipid metabolism (11), N-linked glycosylation (12) and the epithelial-mesenchymal transition (EMT) (18).…”

The co‑treatment of metformin with flavone synergistically induces apoptosis through inhibition of PI3K/AKT pathway in breast cancer cells

“…PI3K/AKT indirectly inhibits mTOR to cause cell cycle arrest and cell apoptosis (4). AKT activates MDM2 indirectly to decrease p53 level and activity, and promote p53 translation and protein stability (5)(6)(7).…”