creators_name: Bhagyaraj, Ella
creators_name: Ahuja, Nancy
creators_name: Kumar, Sumit
creators_name: Tiwari, Drishti
creators_name: Gupta, Shalini
creators_name: Nanduri, Ravikanth
creators_name: Gupta, Pawan
type: article
datestamp: 2019-12-06 15:29:22
lastmod: 2019-12-20 10:25:36
metadata_visibility: show
title: TGF-β induced chemoresistance in liver cancer is modulated by xenobiotic nuclear receptor PXR.
ispublished: pub
subjects: QR
keywords: Hepatocellular carcinoma; chemoresistance; extracellular‐signal‐regulated kinase; nuclear receptors; pregnane X receptor; sorafenib; transforming growth factor-β
note: Copyright of this article belongs to Taylor& Francis 
abstract: Hepatocellular carcinoma appears as an extremely angiogenic solid tumor marked by apoptosis evasion, dysregulated cell cycle and low sensitivity to chemotherapy. TGF-β, a multifunctional cytokine, plays a pleiotropic role in the tumor microenvironment and has implications in cancer drug resistance. The current study provides novel evidence that TGF-β signaling contributes to drug resistance in liver cancer cells by inducing the expression of xenobiotic nuclear receptor PXR. We observed that PXR increases the expression of drug efflux transporters; therefore, accounting for exacerbated drug resistance. Additionally, anti-apoptotic nature of PXR contributes to TGF-β mediated chemoresistance as seen by procaspase-3 and Mcl-1 cellular levels. TGF-β binding to the TGF-β receptor triggers a complex downstream signaling cascade through a non-canonical SMAD-independent ERK pathway that leads to increased PXR expression. Activated ERK activates ETS1 transcription factor which is a critical regulator of endogenous PXR expression in hepatic cells. Loss of function of ETS1 abrogates the TGF-β induced PXR expression. Together these findings indicate that PXR modulates TGF-β induced resistance to chemotherapy in liver cancer cells. This underscores the need for combinatorial approaches with focus on PXR antagonism to improve drug effectiveness in hepatocellular carcinoma. HCC: Hepatocellular Carcinoma; FDA: Food and Drug Administration; TGF-β: Transforming growth factor-β; PXR: Pregnane X receptor; CAR: Constitutive androstane receptor; P-gp/ABCB1: P-glycoproteins/ATP-binding cassette transporter subfamily B member 1; MRP1/ABCC1 and MRP2/ABCC2: Multidrug-resistance associated proteins; BCRP/ABCG2: Breast cancer resistant protein; DMEs: Drug-metabolizing enzymes; CFDA: 5,6-carboxyfluorescein diacetate; ETS1: Transcription factor E26 transformation specific sequence 1.
date: 2019-12
date_type: published
publication: Cell cycle (Georgetown, Tex.)
volume: 18
number: 24
publisher: Taylor& Francis 
pagerange: 3589-3602
refereed: TRUE
issn: 1551-4005
official_url: https://www.tandfonline.com/doi/abs/10.1080/15384101.2019.1693120?journalCode=kccy20
citation:   Bhagyaraj, Ella and Ahuja, Nancy and Kumar, Sumit and Tiwari, Drishti and Gupta, Shalini and Nanduri, Ravikanth and Gupta, Pawan  (2019) TGF-β induced chemoresistance in liver cancer is modulated by xenobiotic nuclear receptor PXR.  Cell cycle (Georgetown, Tex.), 18 (24).  pp. 3589-3602.  ISSN 1551-4005