Department of Medicinal Chemistry, Medical University of Bialystok, 15-222 Bialystok, Poland.
Int J Mol Sci. 2022 Jan 28;23(3):1510. doi: 10.3390/ijms23031510.
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.
非甾体抗炎药 (NSAIDs) 因其对环氧化酶 (COX) 的抑制作用而被认为是癌症预防的治疗药物，因为 COX 在许多类型的癌症中经常过表达。然而，也有研究表明 NSAIDs 在 COX 敲除的癌细胞中引发了促凋亡作用。在这里，我们提出，这组药物可能通过激活 PPARγ 引发抗肿瘤活性，从而诱导脯氨酸脱氢酶/脯氨酸氧化酶 (PRODH/POX) 依赖性细胞凋亡。PRODH/POX 是一种线粒体酶，可催化脯氨酸降解，在此过程中会产生 ATP 或活性氧物种 (ROS)。我们发现 NSAIDs 在乳腺癌 MCF7 细胞中诱导了 PRODH/POX 和 PPARγ 的表达（如 Western Blot 或免疫荧光分析所示）以及细胞毒性（如 MTT、细胞计数分析和 DNA 生物合成分析所示）。同时，NSAIDs 抑制了胶原蛋白的生物合成，支持 PRODH/POX 诱导的 ROS 依赖性细胞凋亡所需的脯氨酸（如凋亡标志物表达增加所示）。这些数据表明，靶向脯氨酸代谢和 PRODH/POX-PPARγ 轴可能被认为是治疗乳腺癌的一种新方法。
