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TGF-β induced chemoresistance in liver cancer is modulated by xenobiotic nuclear receptor PXR.

DIR@IMTECH: CSIR-Institute of Microbial Technology

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Title TGF-β induced chemoresistance in liver cancer is modulated by xenobiotic nuclear receptor PXR.
 
Creator Bhagyaraj, Ella
Ahuja, Nancy
Kumar, Sumit
Tiwari, Drishti
Gupta, Shalini
Nanduri, Ravikanth
Gupta, Pawan
 
Subject QR Microbiology
 
Description 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.
 
Publisher Taylor& Francis
 
Date 2019-12
 
Type Article
PeerReviewed
 
Relation https://www.tandfonline.com/doi/abs/10.1080/15384101.2019.1693120?journalCode=kccy20
http://crdd.osdd.net/open/2507/
 
Identifier 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