TPX2 enhances the transcription factor activation of PXR and enhances the resistance of hepatocellular carcinoma cells to antitumor drugs

Abstract

The pregnane X receptor (PXR) is an important regulator of hepatocellular carcinoma cellular resistance to antitumor drugs. Activation of PXR was modulated by the co-regulators. The target protein for the Xenopus plus end-directed kinesin-like protein (Xklp2) known as TPX2 that was previously considered as a tubulin regulator, also functions as the regulator of some transcription factors and pro-oncogenes in human malignances. However, the actions of TPX2 on PXR and HCC cells are still unclear. In the present study, our results demonstrate that the high expression of endogenous mRNA level of TPX2 not only correlated with the poor prognosis of advanced HCC patients who received sorafenib treatment but also with expression of PXR’s downstream genes, cyp3a4 and/or mdr-1. Results from luciferase and real-time polymerase chain reaction (qPCR) showed that TPX2 leads to enhancement of the transcription factor activation of PXR. Protein–protein interactions between PXR and TPX2 were identified using co-immunoprecipitation. Mechanically, overexpression of TPX2 led to enhancement of PXR recruitment to its downstream gene cyp3a4’s promoter region (the PXRE region) or enhancer region (the XREM region). Treatment of HCC cells with paclitaxel, a microtubule promoter, led to enhancement of the effects of TPX2, whereas vincristine, a microtubule depolymerizing agent caused a decrease in TPX2-associated effects. TPX2 was found to cause acceleration of the metabolism or clearance of sorafenib, a typical tyrosine kinase inhibitor (TKI) in HCC cells and in turn led to the resistance to sorafenib by HCC cells. By establishing novel actions of TXP2 on PXR in HCC cells, the results indicate that TPX2 could be considered a promising therapeutic target to enhance HCC cells sensitivity to antitumor drugs.

TPX2 upregulates MMP13 to promote the progression of lipopolysaccharide-induced osteoarthritis

“…Although it was once considered a microtubule-interacting protein, it has recently been recognized as an important regulator of proliferation and metastasis in human malignant tumors ( Koike et al, 2022 ; Wang et al, 2022 ). The presence of TPX2 was found to trigger accelerated metabolism or clearance of sorafenib, a typical tyrosine kinase inhibitor (TKI), in hepatocellular carcinoma (HCC), leading to resistance of HCC cells to sorafenib ( Wang et al, 2023 ). MMPs are produced by a variety of tissues and cells and belong to the family of zinc-dependent protein hydrolases that function to cleave a variety of ECM proteins ( Cui, Hu & Khalil, 2017 ).…”

Integrated Bioinformatic Analysis Reveals the Oncogenic, Survival, and Prognostic Characteristics of TPX2 in Hepatocellular Carcinoma

“…Several studies have reported the involvement of TPX2 in HCC (Wang et al 2022a;Wang et al 2023a;Huang et al 2019). For example, TPX2 expression is elevated in HCC and its silencing inhibits the malignant behavior of tumor cells (Huang et al 2019).…”