2. Academic Validation
  3. Leptin-derived peptides block leptin-induced proliferation by reducing expression of pro-inflammatory genes in hepatocellular carcinoma cells

Leptin-derived peptides block leptin-induced proliferation by reducing expression of pro-inflammatory genes in hepatocellular carcinoma cells

  • Food Chem Toxicol. 2019 Nov;133:110808. doi: 10.1016/j.fct.2019.110808.
Yih Ho 1,  Shwu-Huey Wang 2,  Yi-Ru Chen 3,  Zi-Lin Li 3,  Yu-Tang Chin 4,  Yu-Chen S H Yang 5,  Yun-Hsuan Wu 6,  Kuan-Wei Su 7,  Hung-Ru Chu 3,  Hsien-Chung Chiu 8,  Dana R Crawford 9,  Ya-Jung Shih 3,  Patricia Grasso 10,  Heng-Yuan Tang 11,  Hung-Yun Lin 12,  Paul J Davis 13,  Jacqueline Whang-Peng 14,  Kuan Wang 3
Affiliations

Affiliations

  • 1 School of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan.
  • 2 Taipei Cancer Center, Taipei Medical University, Taipei, 11031, Taiwan; Core Facility Center, Department of Research Development, Taipei Medical University, Taipei, 11031, Taiwan.
  • 3 Department of Biochemistry and Molecular Cell Biology, School of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei, 11031, Taiwan.
  • 4 Department of Biochemistry and Molecular Cell Biology, School of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, 11031, Taiwan.
  • 5 Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, 11031, Taiwan.
  • 6 Institute of Sociology, Academia Sinica, Taipei, Taiwan.
  • 7 Department of Dentistry, Hsinchu MacKay Memorial Hospital, Hsinchu City, Taiwan.
  • 8 Department of Periodontology, School of Dentistry, National Defense Medical, Center and Tri-Service General Hospital, Taipei, Taiwan.
  • 9 Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA.
  • 10 Department of Medicine, Division of Endocrinology and Metabolism, Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, USA.
  • 11 Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
  • 12 Department of Biochemistry and Molecular Cell Biology, School of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, 11031, Taiwan; Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address: linhy@tmu.edu.tw.
  • 13 Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA; Department of Medicine, Albany Medical College, Albany, NY, USA.
  • 14 Department of Biochemistry and Molecular Cell Biology, School of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, 11031, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
PMID: 31499123 DOI: 10.1016/j.fct.2019.110808
Abstract

The obesity-regulated gene, Leptin, is essential for diet. Leptin resistance causes obesity and related diseases. Certain types of diet are able to decrease Leptin resistance. However, Leptin has been shown to be correlated with inflammation and stimulate proliferation of various cancers. Two synthetic Leptin derivatives (mimetics), OB3 and [D-Leu-4]-OB3, show more effective than Leptin in reducing obesity and diabetes in mouse models. OB3 inhibits leptin-induced proliferation in ovarian Cancer cells. However, effects of these mimetics in hepatocellular carcinoma (HCC) have not been investigated. In the present study, we examined the effects of OB3 and [D-Leu-4]-OB3 on cell proliferation and gene expressions in human HCC cell cultures. In contrast to what was reported for Leptin, OB3 and [D-Leu-4]-OB3 reduced cell proliferation in hepatomas. Both OB3 and [D-Leu-4]-OB3 stimulated expression of pro-apoptotic genes. Both compounds also inhibited expressions of pro-inflammatory, proliferative and metastatic genes and PD-L1 expression. In combination with Leptin, OB3 inhibited leptin-induced cell proliferation and expressions of pro-inflammation-, and proliferation-related genes. Furthermore, the OB3 peptide inhibited phosphoinositide 3-kinase (PI3K) activation which is essential for leptin-induced proliferation in HCC. These results indicate that OB3 and [D-Leu-4]-OB3 may have the potential to reduce leptin-related inflammation and proliferation in HCC cells.

Keywords

Hepatocellular carcinoma cells; Inflammation; Leptin; OB3 peptide; Obesity.

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