Frontiers in Oncology (Mar 2022)
Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity
- Nathalia Araujo,
- James Sledziona,
- Sunil K. Noothi,
- Ravshan Burikhanov,
- Nikhil Hebbar,
- Saptadwipa Ganguly,
- Tripti Shrestha-Bhattarai,
- Beibei Zhu,
- Beibei Zhu,
- Wendy S. Katz,
- Wendy S. Katz,
- Yi Zhang,
- Barry S. Taylor,
- Jinze Liu,
- Li Chen,
- Li Chen,
- Heidi L. Weiss,
- Heidi L. Weiss,
- Daheng He,
- Chi Wang,
- Chi Wang,
- Andrew J. Morris,
- Andrew J. Morris,
- Lisa A. Cassis,
- Lisa A. Cassis,
- Mariana Nikolova-Karakashian,
- Mariana Nikolova-Karakashian,
- Prabhakar R. Nagareddy,
- Olle Melander,
- Olle Melander,
- B. Mark Evers,
- B. Mark Evers,
- Philip A. Kern,
- Philip A. Kern,
- Vivek M. Rangnekar,
- Vivek M. Rangnekar,
- Vivek M. Rangnekar,
- Vivek M. Rangnekar
Affiliations
- Nathalia Araujo
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, United States
- James Sledziona
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, United States
- Sunil K. Noothi
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY, United States
- Ravshan Burikhanov
- Department of Radiation Medicine, University of Kentucky, Lexington, KY, United States
- Nikhil Hebbar
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, United States
- Saptadwipa Ganguly
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, United States
- Tripti Shrestha-Bhattarai
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States
- Beibei Zhu
- Division of Internal Medicine, University of Kentucky, Lexington, KY, United States
- Beibei Zhu
- Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, United States
- Wendy S. Katz
- Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, United States
- Wendy S. Katz
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, United States
- Yi Zhang
- Department of Computer Science, University of Kentucky, Lexington, KY, United States
- Barry S. Taylor
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States
- Jinze Liu
- Department of Computer Science, University of Kentucky, Lexington, KY, United States
- Li Chen
- Division of Internal Medicine, University of Kentucky, Lexington, KY, United States
- Li Chen
- Markey Cancer Center, University of Kentucky, Lexington, KY, United States
- Heidi L. Weiss
- Division of Internal Medicine, University of Kentucky, Lexington, KY, United States
- Heidi L. Weiss
- Markey Cancer Center, University of Kentucky, Lexington, KY, United States
- Daheng He
- 0 Department of Statistics, University of Kentucky, Lexington, KY, United States
- Chi Wang
- Markey Cancer Center, University of Kentucky, Lexington, KY, United States
- Chi Wang
- 1Department of Biostatistics, University of Kentucky, Lexington, KY, United States
- Andrew J. Morris
- Division of Internal Medicine, University of Kentucky, Lexington, KY, United States
- Andrew J. Morris
- Markey Cancer Center, University of Kentucky, Lexington, KY, United States
- Lisa A. Cassis
- Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, United States
- Lisa A. Cassis
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, United States
- Mariana Nikolova-Karakashian
- Markey Cancer Center, University of Kentucky, Lexington, KY, United States
- Mariana Nikolova-Karakashian
- 2Department of Physiology, University of Kentucky, Lexington, KY, United States
- Prabhakar R. Nagareddy
- 3Division of Cardiac Surgery, The Ohio State University, Columbus, OH, United States
- Olle Melander
- 4Department of Clinical Sciences, Lund University, Malmö, Sweden
- Olle Melander
- 5Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden
- B. Mark Evers
- Markey Cancer Center, University of Kentucky, Lexington, KY, United States
- B. Mark Evers
- 6Department of Surgery, University of Kentucky, Lexington, KY, United States
- Philip A. Kern
- Division of Internal Medicine, University of Kentucky, Lexington, KY, United States
- Philip A. Kern
- Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, United States
- Vivek M. Rangnekar
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, United States
- Vivek M. Rangnekar
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY, United States
- Vivek M. Rangnekar
- Department of Radiation Medicine, University of Kentucky, Lexington, KY, United States
- Vivek M. Rangnekar
- Markey Cancer Center, University of Kentucky, Lexington, KY, United States
- DOI
- https://doi.org/10.3389/fonc.2022.860446
- Journal volume & issue
-
Vol. 12
Abstract
Prostate apoptosis response-4 (Par-4) is a tumor suppressor that induces apoptosis in cancer cells. However, the physiological function of Par-4 remains unknown. Here we show that conventional Par-4 knockout (Par-4-/-) mice and adipocyte-specific Par-4 knockout (AKO) mice, but not hepatocyte-specific Par-4 knockout mice, are obese with standard chow diet. Par-4-/- and AKO mice exhibit increased absorption and storage of fat in adipocytes. Mechanistically, Par-4 loss is associated with mdm2 downregulation and activation of p53. We identified complement factor c3 as a p53-regulated gene linked to fat storage in adipocytes. Par-4 re-expression in adipocytes or c3 deletion reversed the obese mouse phenotype. Moreover, obese human subjects showed lower expression of Par-4 relative to lean subjects, and in longitudinal studies, low baseline Par-4 levels denoted an increased risk of developing obesity later in life. These findings indicate that Par-4 suppresses p53 and its target c3 to regulate obesity.
Keywords
