Nandrolone induces a stem cell-like phenotype in human hepatocarcinoma-derived cell line inhibiting mitochondrial
Francesca Agriesti1, Tiziana Tataranni1, Consiglia Pacelli2
1Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, 85028, Rionero in Vulture, Italy.
Abstract:
Nandrolone is a testosterone analogue with anabolic properties commonly abused worldwide, recently utilized also as therapeutic agent in chronic diseases, cancer included. Here we investigated the impact of nandrolone on the metabolic phenotype in HepG2 cell line. The results attained show that pharmacological dosage of nandrolone, slowing cell growth, repressed mitochondrial respiration, inhibited the respiratory chain complexes I and III and enhanced mitochondrial reactive oxygen species (ROS) production. Intriguingly, nandrolone caused a significant increase of stemness-markers in both 2D and 3D cultures, which resulted to be CxIII-ROS dependent. Notably, nandrolone negatively affected differentiation both in healthy hematopoietic and mesenchymal stem cells. Finally, nandrolone administration in mice confirmed the up-regulation of stemness-markers in liver, spleen and kidney. Our observations show, for the first time, that chronic administration of nandrolone, favoring maintenance of stem cells in different tissues would represent a precondition that, in addition to multiple hits, might enhance risk of carcinogenesis raising warnings about its abuse and therapeutic utilization.
Insights
Nandrolone abuse and therapy may increase cancer risk. This anabolic steroid impairs mitochondrial function and stem cell differentiation, promoting stemness markers in cells and tissues.
Area of Science:
- Biochemistry
- Cell Biology
- Toxicology
Background:
- Nandrolone, a testosterone analogue with anabolic properties, is widely abused and explored for therapeutic use in chronic diseases, including cancer.
- Understanding its impact on cellular metabolism and stem cell behavior is crucial given its dual use profile.
Purpose of the Study:
- To investigate the effects of nandrolone on the metabolic phenotype and stemness markers in HepG2 cells.
- To determine the role of mitochondrial reactive oxygen species (ROS) in nandrolone-induced stemness.
- To evaluate nandrolone's impact on stem cell differentiation and its in vivo effects.
Main Methods:
- Utilized HepG2 cell line for metabolic phenotyping.
- Assessed mitochondrial respiration, respiratory chain complex activity, and ROS production.
- Quantified stemness markers in 2D and 3D cell cultures.
- Examined differentiation of hematopoietic and mesenchymal stem cells.
- Administered nandrolone to mice and analyzed stemness markers in liver, spleen, and kidney.
Main Results:
- Pharmacological nandrolone doses slowed cell growth, repressed mitochondrial respiration, and inhibited respiratory chain complexes I and III.
- Nandrolone enhanced mitochondrial ROS production, which was linked to increased stemness markers in cell cultures.
- Nandrolone impaired differentiation in both healthy hematopoietic and mesenchymal stem cells.
- In vivo studies confirmed upregulated stemness markers in mouse liver, spleen, and kidney.
Conclusions:
- Chronic nandrolone administration promotes stemness by impairing mitochondrial function and inhibiting stem cell differentiation.
- This maintenance of stem cells across various tissues may increase cancer risk, warranting caution regarding nandrolone's abuse and therapeutic applications.
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