MDM2 Binding Protein Induces the Resistance of Hepatocellular Carcinoma Cells to Molecular Targeting Agents via Enhancing the Transcription Factor Activity of the Pregnane X Receptor

• Main Authors: Qiyu Jiang, Yan Ma, Jingjing Han, Jingdong Chu, Xuemei Ma, Lijun Shen, Bo Liu, Bo-an Li, Jun Hou, Qian Bi
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-06-01
• Series: Frontiers in Oncology
• Subjects: MDM2 binding protein; Pregnane X receptor; hepatocellular carcinoma; molecular targeting agent; multi-drug resistance; drug metabolism and clearance
• Online Access: https://www.frontiersin.org/articles/10.3389/fonc.2021.715193/full

The MDM2 binding protein (MTBP) has been considered an important regulator of human malignancies. In this study, we demonstrate that the high level of MTBP’s endogenous expression is correlated with poor prognosis of advanced hepatocellular carcinoma (HCC) patients who received sorafenib. MTBP interacted with the Pregnane X receptor (PXR) and enhanced the transcription factor activity of PXR. Moreover, MTBP enhanced the accumulation of PXR in HCC cells’ nuclear and the recruitment of PXR to its downstream gene’s (cyp3a4’s) promoter region. Mechanically, the knockdown of MTBP in MHCC97-H cells with high levels of MTBP decelerated the clearance or metabolism of sorafenib in HCC cells and led to the resistance of HCC cells to sorafenib. Whereas overexpression of MTBP in in MHCC97-L cells with low levels of MTBP showed the opposite trend. By establishing the interaction between MTBP and PXR, our results indicate that MTBP could function as a co-activator of PXR and could be a promising therapeutic target to enhance the sensitivity of HCC cells to molecular targeting agents.