Research Paper Volume 13, Issue 5 pp 6485—6505
Clusterin overexpression in mice exacerbates diabetic phenotypes but suppresses tumor progression in a mouse melanoma model
- 1 Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens 15784, Greece
- 2 Inflammation Research Laboratory, Department of Immunology, Transgenic Technology Laboratory, Hellenic Pasteur Institute, Athens 11521, Greece
- 3 Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens 11521, Greece
- 4 Dipartimento di Medicina e Chirurgia, Universita di Parma, Parma 43125, Italy
- 5 Istituto Nazionale Biostrutture e Biosistemi (I.N.B.B.), Roma 00136, Italy
- 6 Department of Animal and Human Physiology, Faculty of Biology, National and Kapodistrian University of Athens, Athens 15784, Greece
Received: June 11, 2020 Accepted: January 13, 2021 Published: March 10, 2021https://doi.org/10.18632/aging.202788
How to Cite
Copyright: © 2021 Cheimonidi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Clusterin (CLU) is an ATP-independent small heat shock protein-like chaperone, which functions both intra- and extra-cellularly. Consequently, it has been functionally involved in several physiological (including aging), as well as in pathological conditions and most age-related diseases, e.g., cancer, neurodegeneration, and metabolic syndrome. To address CLU function at an in vivo model we established CLU transgenic (Tg) mice bearing ubiquitous or pancreas-targeted CLU overexpression (OE). Our downstream analyses in established Tg lines showed that ubiquitous or pancreas-targeted CLU OE in mice affected antioxidant, proteostatic and metabolic pathways. Targeted OE of CLU in the pancreas, which also resulted in CLU upregulation in the liver likely via systemic effects, increased basal glucose levels in the circulation and exacerbated diabetic phenotypes. Furthermore, by establishing a syngeneic melanoma mouse tumor model we found that ubiquitous CLU OE suppressed melanoma cells growth, indicating a likely tumor suppressor function in early phases of tumorigenesis. Our observations provide in vivo evidence corroborating the notion that CLU is a potential modulator of metabolic and/or proteostatic pathways playing an important role in diabetes and tumorigenesis.
HSF1: Heat Shock transcription Factor-1; HSP: Heat Shock Protein; Keap1: Kelch-like ECH-associated protein 1; Nrf2: NF-E2-related factor 2; PDR: Proteome Damage Responses; PN: Proteostasis Network; ROS: Reactive Oxygen Species; UPS: Ubiquitin Proteasome System.