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
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Additional Information: | Copyright of this article belongs to Taylor& Francis |
| Uncontrolled Keywords: | Hepatocellular carcinoma; chemoresistance; extracellular‐signal‐regulated kinase; nuclear receptors; pregnane X receptor; sorafenib; transforming growth factor-β |
| Subjects: | Q Science > QR Microbiology |
| Depositing User: | Dr. K.P.S.Sengar |
| Date Deposited: | 06 Dec 2019 15:29 |
| Last Modified: | 20 Dec 2019 10:25 |
| URI: | http://crdd.osdd.net/open/id/eprint/2507 |
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