Fructose‐1,6‐bisphosphate induces generation of reactive oxygen species and activation of p53‐dependent cell death in human endometrial cancer cells

• Published in: Journal of applied toxicology 2021-07, Vol.41 (7), p.1050-1062
• Main Authors: Costa, Bruna Pasqualotto, Nassr, Marcella Tornquist, Diz, Fernando Mendonça, Carlessi, Leonardo Pfeiff, Fernandes, Krist Helen Antunes, Nunes, Fernanda Bordignon, Branchini, Gisele, Oliveira, Jarbas Rodrigues
• Format: Article
• Language: English
• Subjects: Anticancer properties; Antineoplastic Agents - pharmacology; Antitumor agents; Apoptosis; Apoptosis - drug effects; Cancer; Cell activation; Cell death; Cell Death - drug effects; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cytotoxicity; Endometrial cancer; Endometrial Neoplasms; Endometrium; Female; Fructose; Fructose - pharmacology; Fructosediphosphates - pharmacology; fructose‐1,6‐bisphosphate; Gene expression; Glycolysis; Humans; Membrane potential; Mitochondria; Mitochondria - drug effects; mitochondrial dysfunction; Mortality; p53 Protein; p53‐dependent cell death; Phagosomes; Reactive oxygen species; Reactive Oxygen Species - metabolism; Tumor Suppressor Protein p53 - genetics
• ISSN: 0260-437X; 1099-1263
• DOI: 10.1002/jat.4091

Fructose‐1,6‐bisphosphate (F1,6BP), an intermediate of the glycolytic pathway, has been found to play a promising anticancer effect; nevertheless, the mechanisms involved remain poorly understood. The present study aimed to evaluate the effect and mechanisms of F1,6BP in a human endometrial cancer cell line (Ishikawa). F1,6BP showed an antiproliferative and non‐cytotoxic effect on endometrial cancer cells. These effects are related to the increase in reactive oxygen species (ROS) levels and mitochondrial membrane potential (ΔΨm). These harmful stimuli trigger the upregulation of the expression of pro‐apoptotic genes (p53 and Bax), leading to the reduction of cell proliferation through inducing programmed cell death by apoptosis. Furthermore, F1,6BP‐treated cells had the formation of autophagosomes induced, as well as a decrease in their proliferative capacity after withdrawing the treatment. Our results demonstrate that F1,6BP acts as an anticancer agent through the generation of mitochondrial instability, loss of cell function, and p53‐dependent cell death. Thus, F1,6BP proves to be a potential molecule for use in the treatment against endometrial cancer. Fructose‐1,6‐bisphosphate (F1,6BP) has been reported as a promising molecule with anticancer activity. Nevertheless, the mechanisms by which F1,6BP exerts this activity remain poorly studied. This study aimed to evaluate the effect and mechanisms of F1,6BP in a human endometrial cancer cell line (Ishikawa). Our results demonstrate that F1,6BP induces antiproliferative effects through mitochondrial dysfunction and increase of ROS levels, which play a critical role in signaling and induction of p53‐dependent death in human endometrial cancer cells.