Nonsteroidal Anti-Inflammatory Drugs as PPARγ Agonists Can Induce PRODH/POX-Dependent Apoptosis in Breast Cancer Cells: New Alternative Pathway in NSAID-Induced Apoptosis

Adam Kazberuk,Jerzy Palka,Magda Chalecka,Arkadiusz Surazynski

doi:10.3390/ijms23031510

Abstract

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 PPARγ, 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 PPARγ 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–PPARγ axis can be considered a novel approach for breast cancer treatment.

Highlights

Academic Editor: Pengfei XuPharmacoepidemiologic data confirm that patients regularly taking nonsteroidal antiinflammatory drugs (NSAIDs) decreased their risks for different types of cancers, such as breast, prostate, lung, and colorectal cancers [1–3]
The studies on the NSAIDs, as ligands of peroxisome proliferator-activated receptor-γ (PPARγ), were undertaken in order to establish the mechanism of their antineoplastic potential
MCF7 breast cancer cells were treated for 24 h with NSAIDs, at the following concentrations: 0.750 mM of ibuprofen; 0.500 mM

Summary

Introduction

Academic Editor: Pengfei XuPharmacoepidemiologic data confirm that patients regularly taking nonsteroidal antiinflammatory drugs (NSAIDs) decreased their risks for different types of cancers, such as breast, prostate, lung, and colorectal cancers [1–3]. The complex regulatory mechanisms involved in cancer growth and metabolism are well recognized, the treatment of cancer is still a challenge in oncology. Some approaches have focused on the anti-inflammatory treatment of cancer [4]. The inflammatory environment is favorable for cancer development. Important in this process are cyclooxygenases (COXs), which are the specific enzymes responsible for prostaglandin synthesis from arachidonic and linoleic acids. Two isoforms of this enzyme were discovered: COX1, constitutively expressed in most of the cells, and COX2, expressed in response to inflammation.

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Discussion

Conclusion