Phthalates promote the invasion of hepatocellular carcinoma cells by enhancing the interaction between Pregnane X receptor and E26 transformation specific sequence 1

Increasing evidence has shown that the metabolism and clearance of molecular targeted agents, such as sorafenib, plays an important role in mediating the resistance of HCC cells to these agents. Metabolism of sorafenib is performed by oxidative metabolism, which is initially mediated by CYP3A4. Thus, targeting CYP3A4 is a promising approach to enhance the sensitivity of HCC cells to chemotherapeutic agents. In the present work, we examined the association between CYP3A4 and the prognosis of HCC patients receiving sorafenib. Using the online tool miRDB, we predicted that has-microRNA-4277 (miR-4277), an online miRNA targets the 3’UTR of the transcript of cyp3a4. Furthermore, overexpression of miR-4277 in HCC cells repressed the expression of CYP3A4 and reduced the elimination of sorafenib in HCC cells. Moreover, miR-4277 enhanced the sensitivity of HCC cells to sorafenib in vitro and in vivo. Therefore, our results not only expand our understanding of CYP3A4 regulation in HCC, but also provide evidence for the use of miR-4277 as a potential therapeutic in advanced HCC.

Section: Methodsmentioning

confidence: 99%

“…Next, sorafenib was extracted from MHCC97-H cells or tumors using the acetonitrile (ACN). The sustaining amount of sorafenib at each time-point was measured using liquid chromatography–mass spectrometry/mass spectrometry (LC-MS/MS) and the in vitro / in vivo half-life of sorafenib was determined ( 18 , 19 , 34 , 35 ).…”

Section: Methodsmentioning

confidence: 99%

Hsa-miR-4277 Decelerates the Metabolism or Clearance of Sorafenib in HCC Cells and Enhances the Sensitivity of HCC Cells to Sorafenib by Targeting cyp3a4

Sun

Jiang

et al. 2021

“…This has been considered an important influencing factor for poor prognoses of patients with advanced HCC ( 1 – 4 ). The PXR (pregnane X receptor) is a member of the nuclear receptors super-family and mainly expresses in the liver and gastrointestinal tract tissues ( 5 , 6 ). It has long been considered to be the regulatory center for the metabolism and detoxification of exogenous drugs and toxicants; results of recent studies show that it is also a key regulator for anti-tumor drug resistance in cancerous cells ( 7 – 10 ).…”

Section: Introductionmentioning

confidence: 99%

“…Upon binding and activating by ligands, PXR can recruit the promoter or enhancer regions to mediate the transcription of its downstream drug-resistance-related genes, inducing cyp3a4 and abcb1 (also named multi-drug resistance 1 [ mdr-1 ]/ATP binding cassette subfamily B member 1 [ABCB1]). It does this by encoding the P-glycoprotein [P-gp]) to mediate the elimination of sorafenib in cancerous cells via the N-oxide metabolism of sorafenib or by decreasing the intracellular accumulation of it, which in turn reduces the clinical efficacy or resistance of the drug during treatment ( 5 – 10 ).…”

Section: Introductionmentioning

confidence: 99%

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

Jiang

Han³

et al. 2021

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.

“…Liver cancer is one of the leading causes of cancer-related deaths worldwide ( 1 – 3 ). Hepatocellular carcinoma (HCC) accounts for the vast majority of liver cancers, representing nearly 75% of all primary liver tumors ( 4 – 6 ).…”

Section: Introductionmentioning

confidence: 99%

CK-3, A Novel Methsulfonyl Pyridine Derivative, Suppresses Hepatocellular Carcinoma Proliferation and Invasion by Blocking the PI3K/AKT/mTOR and MAPK/ERK Pathways

Liu

et al. 2021

Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis that highly expresses phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (ERK). The PI3K/AKT/mTOR and MAPK/ERK signaling pathways play a crucial role in HCC tumor formation, cell cycle, apoptosis and survival. However, no effective targeted therapies against these pathways is available, mainly due to the extensive and complex negative feedback loops between them. Here we used CK-3, a dual blocker of the PI3K/AKT/mTOR and MAPK/ERK pathways, against HCC cell lines to verify its anti-tumor activity in vitro. CK-3 exhibited cytotoxic activity against HCC, as demonstrated with MTT and colony formation assays. The anti-metastatic potential of CK-3 was demonstrated with wound healing and cell invasion assays. The ability of CK-3 to block both the PI3K/AKT/mTOR and MAPK/ERK pathways was also confirmed. CK-3 induced the apoptosis of Hep3B cells, while Bel7402 cells died via mitotic catastrophe (MC). Oral administration of CK-3 also inhibited the subcutaneous growth of BEL7402 cells in nude mice. Simultaneous PI3K/AKT/mTOR and MAPK/ERK pathway inhibition with CK-3 may be superior to single pathway monotherapies by inhibiting their feedback-regulation, and represents a potential treatment for HCC.