Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/ijms23031510
Keywords
proline; proline oxidase; proline dehydrogenase; NSAIDS; PPAR; COX; apoptosis; breast cancer; oxidative stress
Funding
- National Science Centre of Poland [2017/27/N/NZ7/02370]
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Nonsteroidal anti-inflammatory drugs (NSAIDs) may induce apoptosis through the activation of PPAR gamma and the proline metabolism enzyme PRODH/POX in breast cancer cells.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered to be therapeutics in cancer prevention because of their inhibitory effect on cyclooxygenases (COX), which are frequently overexpressed in many types of cancer. However, it was also demonstrated that NSAIDs provoked a proapoptotic effect in COX knocked-out cancer cells. Here, we suggest that this group of drugs may provoke antineoplastic activity through the activation of PPAR gamma, which induces proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis. PRODH/POX is a mitochondrial enzyme that catalyzes proline degradation, during which ATP or reactive oxygen species (ROS) are generated. We have found that NSAIDs induced PRODH/POX and PPAR gamma expressions (as demonstrated by Western Blot or immunofluorescence analysis) and cytotoxicity (as demonstrated by MTT, cytometric assay, and DNA biosynthesis assay) in breast cancer MCF7 cells. Simultaneously, the NSAIDs inhibited collagen biosynthesis, supporting proline for PRODH/POX-induced ROS-dependent apoptosis (as demonstrated by an increase in the expression of apoptosis markers). The data suggest that targeting proline metabolism and the PRODH/POX-PPAR gamma axis can be considered a novel approach for breast cancer treatment.
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