Nrf3 Promotes 5-FU Resistance in Colorectal Cancer Cells via the NF-κB/BCL-2 Signaling Pathway In Vitro and In Vivo.

Bi-Qing Cai,Wei Hou,Jia Zhao,Wan-Meng Chen,Jian-Cai Tang,Dali Zheng

doi:10.1155/2021/9355555

Abstract

Increasing evidence indicates that nuclear factor, erythroid 2-like 3 (Nrf3) is connected with tumorigenesis. However, the relationship between Nrf3 and tumor drug resistance remains elusive. In this study, we investigated the effect and mechanism of action by which Nrf3 regulated the sensitivity of colon cancer cells to 5-fluorouracil (5-FU). We found Nrf3 was significantly increased in colon cancer tissues. Furthermore, we observed that Nrf3 knockdown and overexpression can significantly affect the sensitivity of colon cancer cells to 5-FU in vitro and in vivo. Moreover, Nrf3 promoted the expression of RELA, P-RELA, and BCL-2. Inhibition of NF-κB partly reversed the effects of Nrf3 overexpression, resulting in the resistance of colon cancer cells to 5-FU. Overall, the study revealed that Nrf3 was connected to the sensitivity of colon cancer cells to 5-FU, and its possible mechanism was related to the NF-κB signaling pathway, which provided a new target for overcoming the resistance of colon cancer cells to 5-FU.

Highlights

Colorectal cancer (CRC) is the third most common cancer in the world [1]. ere are about 1.36 million new cases and 700,000 deaths per year worldwide because of CRC
Extensive reports have shown that the expression of Nrf3 was remarkably increased in CRC tissues compared to normal tissues and promoted CRC cell proliferation [10, 11]. e mechanisms through which Nrf3 regulates various cellular processes have partly been elucidated by some reports. ese studies provided some evidence that Nrf3 may play a vital role in the evolution and development of the tumor [8, 12]
We found that the expression of Nrf3 was higher in the colon cancer tissues than in normal tissues (Figure 1; Table 1). e high level of Nrf3 expression is not connected with the clinical correlation index (Table 2)

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer in the world [1]. ere are about 1.36 million new cases and 700,000 deaths per year worldwide because of CRC. Surgical resection is the primary choice, chemotherapy has played an important role in treating CRC, especially for patients with unresectable disease [2]. Approximately 40% of patients developed drug resistance leading to therapy failure [3]. Nrf mainly exists in the cytoplasm; translocates into the nucleus under external stimuli, such as stress; and promotes target gene translation [5]. Previous studies implied that Nrf may be involved in various cellular processes, including carcinogenesis, inflammation, and antioxidative stress [6–9]. E mechanisms through which Nrf regulates various cellular processes have partly been elucidated by some reports. Ese studies provided some evidence that Nrf may play a vital role in the evolution and development of the tumor [8, 12]. There are no reports on the relationship between Nrf and 5-FU resistance

Methods

Results

Conclusion