Tags

Type your tag names separated by a space and hit enter

YAP Inhibition by Nuciferine via AMPK-Mediated Downregulation of HMGCR Sensitizes Pancreatic Cancer Cells to Gemcitabine.
Biomolecules 2019; 9(10)B

Abstract

Nuciferine, a major aporphine alkaloid constituent of lotus leaves, is a raw material for obesity treatment. Extensive studies have revealed that obesity is associated with pancreatic cancer (PC). However, it has not been clarified whether nuciferine could be used in PC treatment or prevention. Here, we show that nuciferine could enhance the sensitivity of PC cells to gemcitabine in both cultured cells and the xenograft mouse model. The mechanism study demonstrated that nuciferine induced YAP Ser127 phosphorylation [pYAP(Ser127)] through AMPK-mediated 3-hydroxy-3-methyl-glutaryl-coA reductase (HMGCR) downregulation. Remarkably, wild-type YAP overexpression or YAP Ser127 mutant could resist to nuciferine and no longer sensitize PC cells to gemcitabine. Knockdown of AMPK attenuated pYAP(Ser127) induced by nuciferine. Moreover, knockdown of AMPK reversed nuciferine-mediated HMGCR downregulation. Notably, HMGCR inhibiting could restrain YAP by phosphorylation Ser 127, and therefore enhance the efficiency of gemcitabine in PC cells. In line with this consistent, overexpression of HMGCR reduced growth inhibition caused by nuciferine and/or gemcitabine treatment in PC cells. In summary, these results provide an effective supplementary agent and suggest a therapeutic strategy to reduce gemcitabine resistance in PC.

Authors+Show Affiliations

The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, Yantai 264003, China. zhouling-2007-ok@163.com. Key Laboratory of Tumor Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai 264003, China. zhouling-2007-ok@163.com.The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, Yantai 264003, China. byylwqy@163.com.The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, Yantai 264003, China. zhanghan343231409@163.com.Key Laboratory of Tumor Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai 264003, China. youjie1979@163.com.Key Laboratory of Tumor Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai 264003, China. shuyangxie@aliyun.com.The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, Yantai 264003, China. xumaolei@bzmc.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31627466

Citation

Zhou, Ling, et al. "YAP Inhibition By Nuciferine Via AMPK-Mediated Downregulation of HMGCR Sensitizes Pancreatic Cancer Cells to Gemcitabine." Biomolecules, vol. 9, no. 10, 2019.
Zhou L, Wang Q, Zhang H, et al. YAP Inhibition by Nuciferine via AMPK-Mediated Downregulation of HMGCR Sensitizes Pancreatic Cancer Cells to Gemcitabine. Biomolecules. 2019;9(10).
Zhou, L., Wang, Q., Zhang, H., Li, Y., Xie, S., & Xu, M. (2019). YAP Inhibition by Nuciferine via AMPK-Mediated Downregulation of HMGCR Sensitizes Pancreatic Cancer Cells to Gemcitabine. Biomolecules, 9(10), doi:10.3390/biom9100620.
Zhou L, et al. YAP Inhibition By Nuciferine Via AMPK-Mediated Downregulation of HMGCR Sensitizes Pancreatic Cancer Cells to Gemcitabine. Biomolecules. 2019 Oct 17;9(10) PubMed PMID: 31627466.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - YAP Inhibition by Nuciferine via AMPK-Mediated Downregulation of HMGCR Sensitizes Pancreatic Cancer Cells to Gemcitabine. AU - Zhou,Ling, AU - Wang,Qiaoyun, AU - Zhang,Han, AU - Li,Youjie, AU - Xie,Shuyang, AU - Xu,Maolei, Y1 - 2019/10/17/ PY - 2019/09/08/received PY - 2019/10/07/revised PY - 2019/10/14/accepted PY - 2019/10/20/entrez KW - 3-hydroxy-3-methyl-glutaryl-coA reductase KW - AMP-activation protein kinase KW - Nuciferine KW - Yes-associated protein KW - gemcitabine KW - pancreatic cancer JF - Biomolecules JO - Biomolecules VL - 9 IS - 10 N2 - Nuciferine, a major aporphine alkaloid constituent of lotus leaves, is a raw material for obesity treatment. Extensive studies have revealed that obesity is associated with pancreatic cancer (PC). However, it has not been clarified whether nuciferine could be used in PC treatment or prevention. Here, we show that nuciferine could enhance the sensitivity of PC cells to gemcitabine in both cultured cells and the xenograft mouse model. The mechanism study demonstrated that nuciferine induced YAP Ser127 phosphorylation [pYAP(Ser127)] through AMPK-mediated 3-hydroxy-3-methyl-glutaryl-coA reductase (HMGCR) downregulation. Remarkably, wild-type YAP overexpression or YAP Ser127 mutant could resist to nuciferine and no longer sensitize PC cells to gemcitabine. Knockdown of AMPK attenuated pYAP(Ser127) induced by nuciferine. Moreover, knockdown of AMPK reversed nuciferine-mediated HMGCR downregulation. Notably, HMGCR inhibiting could restrain YAP by phosphorylation Ser 127, and therefore enhance the efficiency of gemcitabine in PC cells. In line with this consistent, overexpression of HMGCR reduced growth inhibition caused by nuciferine and/or gemcitabine treatment in PC cells. In summary, these results provide an effective supplementary agent and suggest a therapeutic strategy to reduce gemcitabine resistance in PC. SN - 2218-273X UR - https://www.unboundmedicine.com/medline/citation/31627466/YAP_Inhibition_by_Nuciferine_via_AMPK-Mediated_Downregulation_of_HMGCR_Sensitizes_Pancreatic_Cancer_Cells_to_Gemcitabine L2 - http://www.mdpi.com/resolver?pii=biom9100620 DB - PRIME DP - Unbound Medicine ER -