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Background

Limited by difficulties in early detection and availabilities of effective treatments, pancreatic cancer is a highly malignant disease with poor prognosis. Nuclear receptors are a family of ligand‐dependent transcription factors that are highly druggable therapeutic targets playing critical roles in human physiological and pathological development, including cancer. In this study, we explored the therapeutic potential as well as the molecular mechanisms of liver X receptor (LXR) agonist GW3965 in pancreatic cancer.

Methods

Soft‐agar colony formation assay, xenograft tumors, Oligonucleotide microarray, Reverse transcription real‐time polymerase chain reaction, Western immunoblotting and Immunohistochemistry were used in this study.

Results

We demonstrated pleotropic in vitro activities of GW3965 in pancreatic cell lines MIA PaCa‐2 and BXPC3 including reduction of cell viability, inhibition of cell proliferation, stimulation of cell death, and suppression of colony formation, which translated to significant inhibition of xenograft tumor growth in vitro. By mapping the gene expression profiles, we identified the up‐regulations of 188 and the down‐regulations of 92 genes common to both cell lines following GW3965 treatment. Genes responsive to GW3965 represent a variety of biological pathways vital for multiple cellular functions. Specifically, we identified that the activating transcription factor 4/thioredoxin‐interacting protein/regulated in development and DNA damage responses 1/mechanistic target of rapamycin (ATF4/TXNIP/REDD1/mTOR) signaling critically controls GW3965‐mediated regulation of cell proliferation/death. The significance of the ATF4/TXNIP/REDD1/mTOR pathway was further supported by associated expressions in xenograft tumors as well as human pancreatic cancer samples.

Conclusions

This study provides the pre‐clinical evidence that LXR agonist is a promising therapy for pancreatic cancer.


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ATF4/TXNIP/REDD1/mTOR signaling mediates the antitumor activities of liver X receptor in pancreatic cancers

Show Author's information Zhikang Chen1,2,3,4Xiaobo Lai5Hui Ding6Aijun Zhang7Yufei Sun1,2,3,4Jianhua Ling8Paul J. Chiao8Zihua Chen1,2,3,4( )Xuefeng Xia9 ( )
The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Changsha, Hunan, China
Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standardization, Changsha, Hunan, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
Guangzhou First People's Hospital, The Second Affiliated Hospital of South China University of Technology, Guangzhou, Guangdong, China
Hainan Eye Hospital and Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‐Sen University, Haikou, Hainan, China
Houston Methodist Research Institute, Houston, Texas, USA
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
GenePlus‐Beijing Institute, Beijing, China

Abstract

Background

Limited by difficulties in early detection and availabilities of effective treatments, pancreatic cancer is a highly malignant disease with poor prognosis. Nuclear receptors are a family of ligand‐dependent transcription factors that are highly druggable therapeutic targets playing critical roles in human physiological and pathological development, including cancer. In this study, we explored the therapeutic potential as well as the molecular mechanisms of liver X receptor (LXR) agonist GW3965 in pancreatic cancer.

Methods

Soft‐agar colony formation assay, xenograft tumors, Oligonucleotide microarray, Reverse transcription real‐time polymerase chain reaction, Western immunoblotting and Immunohistochemistry were used in this study.

Results

We demonstrated pleotropic in vitro activities of GW3965 in pancreatic cell lines MIA PaCa‐2 and BXPC3 including reduction of cell viability, inhibition of cell proliferation, stimulation of cell death, and suppression of colony formation, which translated to significant inhibition of xenograft tumor growth in vitro. By mapping the gene expression profiles, we identified the up‐regulations of 188 and the down‐regulations of 92 genes common to both cell lines following GW3965 treatment. Genes responsive to GW3965 represent a variety of biological pathways vital for multiple cellular functions. Specifically, we identified that the activating transcription factor 4/thioredoxin‐interacting protein/regulated in development and DNA damage responses 1/mechanistic target of rapamycin (ATF4/TXNIP/REDD1/mTOR) signaling critically controls GW3965‐mediated regulation of cell proliferation/death. The significance of the ATF4/TXNIP/REDD1/mTOR pathway was further supported by associated expressions in xenograft tumors as well as human pancreatic cancer samples.

Conclusions

This study provides the pre‐clinical evidence that LXR agonist is a promising therapy for pancreatic cancer.

Keywords: pancreatic cancer, signaling pathways, GW3965, liver X receptor, nuclear receptors

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Publication history

Received: 28 February 2022
Accepted: 16 May 2022
Published: 30 June 2022
Issue date: June 2022

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© 2022 The Authors.

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