Proline Dehydrogenase/Proline Oxidase (PRODH/POX) Is Involved in the Mechanism of Metformin-Induced Apoptosis in C32 Melanoma Cell Line

Ościłowska, Ilona; Rolkowski, Karol; Baszanowska, Weronika; Huynh, Thi Yen Ly; Lewoniewska, Sylwia; Nizioł, Magdalena; Sawicka, Magdalena; Bielawska, Katarzyna; Szoka, Paweł; Miltyk, Wojciech; Pałka, Jerzy

doi:10.3390/ijms23042354

Cited by 10 publications

(9 citation statements)

References 69 publications

(89 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It seems that in the melanoma cells with a high capacity to utilize proline for collagen biosynthesis, the proline concentration is not high enough to induce extrinsic apoptosis. However, the stimulation of PRODH/POX by MET in melanoma cells induced ROS-dependent apoptosis, while PRODH/POX knockout abolished the effect ( Oscilowska et al, 2022 ). A similar effect was found in MCF-7 cells treated with non-steroidal anti-inflammatory drugs ( Kazberuk et al, 2022b ).…”

Section: Discussionmentioning

confidence: 99%

Metformin Induces PRODH/POX-Dependent Apoptosis in Breast Cancer Cells

Huynh

Ościłowska

Szoka

et al. 2022

Front. Mol. Biosci.

Self Cite

View full text Add to dashboard Cite

Although the antineoplastic activity of metformin (MET) is well established, the underlying mechanism of the activity is not understood. Since MET activates AMP kinase (AMPK) and proline dehydrogenase/proline oxidase (PRODH/POX) is stimulated by AMPK ligands (implicated in the regulation of cancer cell survival/apoptosis), the effect of MET on PRODH/POX-dependent apoptosis in wild-type MCF-7 cells (MCF-7WT) and POX knockdown MCF-7 cells (MCF-7crPOX cells) was studied. PRODH/POX catalyzes proline degradation generating ROS-induced apoptosis or autophagy. Availability of proline for PRODH/POX functions is regulated by the activity of prolidase (enzyme releasing proline from imidodipeptides), collagen biosynthesis (process consuming proline), and metabolism of proline, ornithine, and glutamic acid. We have found that MET is cytotoxic for MCF-7 cells (IC50∼17 mM), and to the lower extent for MCF-7crPOX cells (IC50∼28 mM). In MCF-7WT cells, the effect was accompanied by the inhibition of DNA biosynthesis, collagen biosynthesis, stimulation of ROS formation, AMPKα phosphorylation, and expression of prolidase, p53, caspase 8, caspase 9, and cleaved PARP. In MET-treated MCF-7crPOX cells, the processes were less affected than in MCF-7WT cells and the expression of caspase 9 was decreased, while cleaved caspase 8 and cleaved PARP were not detected. The effects were accompanied by an increase in the prolidase activity and proline concentration. The mechanism for MET-induced apoptosis involves the up-regulation of prolidase activity and a decrease in collagen biosynthesis contributing to an increase in the concentration of substrate (proline) for PRODH/POX-dependent ROS formation and activation of caspases −9 and −8. The data suggest that PRODH/POX participates in the MET-induced intrinsic and extrinsic apoptosis in MCF-7 cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Metformin Induces PRODH/POX-Dependent Apoptosis in Breast Cancer Cells

Huynh

Ościłowska

Szoka

et al. 2022

Front. Mol. Biosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…It seems that in the melanoma cells with high capacity to utilize proline for collagen biosynthesis, the proline concentration is not enough high to induce extrinsic apoptosis. However, stimulation of PRODH/POX by metformin in melanoma cells induced ROS-dependent apoptosis, while PRODH/POX knockout abolished the effect [ 96 ]. Our other studies on MCF-7 and MDA-MB-231 cells highlighted the role of estrogens and estrogen receptors (ERα and ERβ) in PRODH/POX-dependent apoptosis [ 97 ].…”

Section: Discussionmentioning

confidence: 99%

NSAIDs Induce Proline Dehydrogenase/Proline Oxidase-Dependent and Independent Apoptosis in MCF7 Breast Cancer Cells

Kazberuk

Chalecka

Pałka

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

Non-steroidal anti-inflammatory drugs (NSAIDs) are considered in cancer therapy for their inhibitory effect on cyclooxygenase-2 (COX-2), which is overexpressed in most cancers. However, we found that NSAIDs as ligands of peroxisome proliferator-activated receptor-γ (PPARγ)-induced apoptosis independent of the COX-2 inhibition, and the process was mediated through activation of proline dehydrogenase/proline oxidase (PRODH/POX)-dependent generation of reactive oxygen species (ROS). This mitochondrial enzyme converts proline to ∆1-pyrroline-5-carboxylate (P5C) during which ATP or ROS is generated. To confirm the role of PRODH/POX in the mechanism of NSAID-induced apoptosis we obtained an MCF7 CRISPR/Cas9 PRODH/POX knockout breast cancer cell model (MCF7POK-KO). Interestingly, the studied NSAIDs (indomethacin and diclofenac) in MCF7POK-KO cells contributed to a more pronounced pro-apoptotic phenotype of the cells than in PRODH/POX-expressing MCF7 cells. The observed effect was independent of ROS generation, but it was related to the energetic disturbances in the cells as shown by an increase in the expression of AMPKα (sensor of cell energy status), GLUD1/2 (proline producing enzyme from glutamate), prolidase (proline releasing enzyme), PPARδ (growth supporting transcription factor) and a decrease in the expression of proline cycle enzymes (PYCR1, PYCRL), mammalian target of rapamycin (mTOR), and collagen biosynthesis (the main proline utilizing process). The data provide evidence that the studied NSAIDs induce PRODH/POX-dependent and independent apoptosis in MCF7 breast cancer cells.

show abstract

“…Changes in the MAPK and PI3K pathways are more commonly attributed to the occurrence of melanoma and can significantly affect the metabolism of melanoma cells. Additionally, the AMP-activated protein kinase (AMPK) pathway involved in mitochondrial function has been associated with the metabolism of melanoma cells [ 176 , 177 ]. AMPK is a well-known metabolic receptor that maintains cellular energy homeostasis.…”

Section: Mitochondria and Melanomamentioning

confidence: 99%

The role of mitochondria in the resistance of melanoma to PD-1 inhibitors

Du,

Yang,

Liu

et al. 2023

J Transl Med

View full text Add to dashboard Cite

Malignant melanoma is one of the most common tumours and has the highest mortality rate of all types of skin cancers worldwide. Traditional and novel therapeutic approaches, including surgery, targeted therapy and immunotherapy, have shown good efficacy in the treatment of melanoma. At present, the mainstay of treatment for melanoma is immunotherapy combined with other treatment strategies. However, immune checkpoint inhibitors, such as PD-1 inhibitors, are not particularly effective in the clinical treatment of patients with melanoma. Changes in mitochondrial function may affect the development of melanoma and the efficacy of PD-1 inhibitors. To elucidate the role of mitochondria in the resistance of melanoma to PD-1 inhibitors, this review comprehensively summarises the role of mitochondria in the occurrence and development of melanoma, targets related to the function of mitochondria in melanoma cells and changes in mitochondrial function in different cells in melanoma resistant to PD-1 inhibitors. This review may help to develop therapeutic strategies for improving the clinical response rate of PD-1 inhibitors and prolonging the survival of patients by activating mitochondrial function in tumour and T cells.

show abstract

Proline Dehydrogenase/Proline Oxidase (PRODH/POX) Is Involved in the Mechanism of Metformin-Induced Apoptosis in C32 Melanoma Cell Line

Cited by 10 publications

References 69 publications

Metformin Induces PRODH/POX-Dependent Apoptosis in Breast Cancer Cells

Metformin Induces PRODH/POX-Dependent Apoptosis in Breast Cancer Cells

NSAIDs Induce Proline Dehydrogenase/Proline Oxidase-Dependent and Independent Apoptosis in MCF7 Breast Cancer Cells

The role of mitochondria in the resistance of melanoma to PD-1 inhibitors

Contact Info

Product

Resources

About