Proline oxidase silencing induces proline-dependent pro-survival pathways in MCF-7 cells
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Ilona Zareba1, Katarzyna Celinska-Janowicz2, Arkadiusz Surazynski1, Wojciech Miltyk2 and Jerzy Palka1
1Department of Medicinal Chemistry, Medical University of Bialystok, 15-222 Bialystok, Poland
2Department of Pharmaceutical Analysis, Medical University of Bialystok, 15-222 Bialystok, Poland
Jerzy Palka, email: firstname.lastname@example.org
Keywords: MCF-7 breast cancer cells; proline dehydrogenase/proline oxidase; apoptosis; autophagy; proline
Received: July 07, 2017 Accepted: February 01, 2018 Published: February 09, 2018
Proline degradation by proline dehydrogenase/proline oxidase (PRODH/POX) contributes to apoptosis or autophagy. The identification of specific pathway of apoptosis/survival regulation is the aim of this study. We generated knocked-down PRODH/POX MCF-7 breast cancer cells (MCF-7shPRODH/POX). PRODH/POX silencing did not affect cell viability. However, it contributed to decrease in DNA and collagen biosynthesis, increase in prolidase activity and intracellular proline concentration as well as increase in the expression of iNOS, NF-κB, mTOR, HIF-1α, COX-2, AMPK, Atg7 and Beclin-1 in MCF-7shPRODH/POX cells. In these cells, glycyl-proline (GlyPro, substrate for prolidase) further inhibited DNA and collagen biosynthesis, maintained high prolidase activity, intracellular concentration of proline and up-regulated HIF-1α, AMPK, Atg7 and Beclin-1, compared to GlyPro-treated MCF-7 cells. In MCF-7 cells, GlyPro increased collagen biosynthesis, concentration of proline and expression of caspase-3, cleaved caspases -3 and -9, iNOS, NF-κB, COX-2 and AMPKβ. PRODH/POX knock-down contributed to pro-survival autophagy pathways in MCF-7 cells and GlyPro-derived proline augmented this process. However, GlyPro induced apoptosis in PRODH/POX-expressing MCF-7 cells as detected by up-regulation of active caspases -3 and -9. The data suggest that PRODH/POX silencing induces autophagy in MCF-7 cells and GlyPro-derived proline supports this process.
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