ATF4/TXNIP/REDD1/mTOR signaling mediates the antitumor activities of liver X receptor in pancreatic cancers
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 playi...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-06-01
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| Series: | Cancer Innovation |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cai2.12 |
| _version_ | 1811233209928646656 |
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| author | Zhikang Chen Xiaobo Lai Hui Ding Aijun Zhang Yufei Sun Jianhua Ling Paul J. Chiao Zihua Chen Xuefeng Xia |
| author_facet | Zhikang Chen Xiaobo Lai Hui Ding Aijun Zhang Yufei Sun Jianhua Ling Paul J. Chiao Zihua Chen Xuefeng Xia |
| author_sort | Zhikang Chen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T11:16:48Z |
| format | Article |
| id | doaj.art-6333fd30f52643d4961f44b5cbdd2705 |
| institution | Directory Open Access Journal |
| issn | 2770-9183 |
| language | English |
| last_indexed | 2024-04-12T11:16:48Z |
| publishDate | 2022-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Innovation |
| spelling | doaj.art-6333fd30f52643d4961f44b5cbdd27052022-12-22T03:35:28ZengWileyCancer Innovation2770-91832022-06-0111556910.1002/cai2.12ATF4/TXNIP/REDD1/mTOR signaling mediates the antitumor activities of liver X receptor in pancreatic cancersZhikang Chen0Xiaobo Lai1Hui Ding2Aijun Zhang3Yufei Sun4Jianhua Ling5Paul J. Chiao6Zihua Chen7Xuefeng Xia8The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor Changsha Hunan ChinaGuangzhou First People's Hospital The Second Affiliated Hospital of South China University of Technology Guangzhou Guangdong ChinaHainan Eye Hospital and Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center Sun Yat‐Sen University Haikou Hainan ChinaHouston Methodist Research Institute Houston Texas USAThe Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor Changsha Hunan ChinaDepartment of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Houston Texas USADepartment of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Houston Texas USAThe Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor Changsha Hunan ChinaGenePlus‐Beijing Institute Beijing ChinaAbstract 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.https://doi.org/10.1002/cai2.12GW3965liver X receptornuclear receptorspancreatic cancersignaling pathways |
| spellingShingle | Zhikang Chen Xiaobo Lai Hui Ding Aijun Zhang Yufei Sun Jianhua Ling Paul J. Chiao Zihua Chen Xuefeng Xia ATF4/TXNIP/REDD1/mTOR signaling mediates the antitumor activities of liver X receptor in pancreatic cancers Cancer Innovation GW3965 liver X receptor nuclear receptors pancreatic cancer signaling pathways |
| title | ATF4/TXNIP/REDD1/mTOR signaling mediates the antitumor activities of liver X receptor in pancreatic cancers |
| title_full | ATF4/TXNIP/REDD1/mTOR signaling mediates the antitumor activities of liver X receptor in pancreatic cancers |
| title_fullStr | ATF4/TXNIP/REDD1/mTOR signaling mediates the antitumor activities of liver X receptor in pancreatic cancers |
| title_full_unstemmed | ATF4/TXNIP/REDD1/mTOR signaling mediates the antitumor activities of liver X receptor in pancreatic cancers |
| title_short | ATF4/TXNIP/REDD1/mTOR signaling mediates the antitumor activities of liver X receptor in pancreatic cancers |
| title_sort | atf4 txnip redd1 mtor signaling mediates the antitumor activities of liver x receptor in pancreatic cancers |
| topic | GW3965 liver X receptor nuclear receptors pancreatic cancer signaling pathways |
| url | https://doi.org/10.1002/cai2.12 |
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