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- Title
Proline Dehydrogenase/Proline Oxidase (PRODH/POX) Is Involved in the Mechanism of Metformin-Induced Apoptosis in C32 Melanoma Cell Line.
- Authors
Oscilowska, Ilona; Rolkowski, Karol; Baszanowska, Weronika; Huynh, Thi Yen Ly; Lewoniewska, Sylwia; Nizioł, Magdalena; Sawicka, Magdalena; Bielawska, Katarzyna; Szoka, Paweł; Miltyk, Wojciech; Palka, Jerzy
- Abstract
The role of proline dehydrogenase/proline oxidase (PRODH/POX) in the mechanism of antineoplastic activity of metformin (MET) was studied in C32 melanoma cells. PRODH/POX is a mitochondrial enzyme-degrading proline that is implicated in the regulation of cancer cell survival/apoptosis. The enzyme is activated by AMP kinase (AMPK). It has been found that MET induced a significant decrease in cell viability and DNA biosynthesis accompanied by an increase in the expressions of AMPK and PRODH/POX in C32 cells. The mechanism for MET-dependent cytotoxicity on C32 cells was found at the level of PRODH/POX-induced ROS generation and activation of Caspase-3 and Caspase-9 expressions in these cells. The effects were not observed in MET-treated PRODH/POX knock-out C32 cells. Of interest is an MET-dependent increase in the concentration of proline, which is a substrate for PRODH/POX. This phenomenon is due to the MET-dependent inhibition of collagen biosynthesis, which is the main proline-utilizing process. It has been found that the underlying mechanism of anticancer activity of MET involves the activation of AMPK, PRODH/POX, increase in the cytoplasmic concentration of proline, inhibition of collagen biosynthesis, and stimulation of PRODH/POX-dependent ROS generation, which initiate the apoptosis of melanoma cells.
- Subjects
METFORMIN; PROLINE; CELL lines; MELANOMA; CELL survival; CELLULAR control mechanisms; CANCER cells
- Publication
International Journal of Molecular Sciences, 2022, Vol 23, Issue 4, p2354
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms23042354