Proline-Dependent Induction of Apoptosis in Oral Squamous Cell Carcinoma (OSCC)—The Effect of Celecoxib

Abstract

Background: Oral squamous cell carcinoma remains a significant worldwide public health challenge, associated with high morbidity and mortality. Treatment of this type of cancer lacks effective medication. Moreover, there are very few specific biomarkers that are useful in early diagnosis or treatment optimisation. Proline metabolism may prove to be of importance in the search for new treatment modalities. Methods: To evaluate the significance of proline metabolism in the development of oral cancer, proline concentration was assessed in oral cancer tissue and normal oral mucosa. The results were compared to the clinical stage and histological grade of the tumours. Moreover, the expression of proteins involved in proline metabolism via proline dehydrogenase/oxidase (PRODH/POX, PPARγ, HIF1-α) was determined. In the next stage of the study, conducted on cell lines of tongue cancer treated with celecoxib, the aforementioned factors involved in proline metabolism were evaluated. Cellular viability and cell proliferation, as well as apoptosis, were also assessed. Results: Our research results indicate that a high intracellular proline concentration and expression of factors involved in its metabolism correlate with the clinical stage and histological grade of oral cancer. Moreover, we are the first researchers to demonstrate that celecoxib can affect proline metabolism, causing an increase in pro-apoptotic factors (PRODH/POX, PPARγ), reducing the expression of HIF-1α and activating apoptosis. Conclusions: Proline metabolism, due to its involvement in the process of apoptosis, can be of great importance in anticancer therapy. It appears that celecoxib, which influences the PRODH/POX pathway, may be a promising therapeutic compound in oral cancer treatment.

The Janus-like role of proline metabolism in cancer

“…Indeed, COX-2 inhibitors, such as celecoxib, have widespread anticancer activities and can induce apoptosis in cancer cells 78 . Of note, preliminary indications in oral squamous cell carcinoma suggest that celecoxib treatment increases levels of PRODH1, although it has yet to be established whether such an increase contributes to celecoxibmediated suppression of cell growth and viability 79 . In agreement with its role as tumor suppressor gene, reduced expression of PRODH1 has been reported in several cancers, with more consistent downregulation observed in renal cancers and cancers arising from the digestive tract 64,71,76,[79][80][81] .…”

“…Preliminary data suggest that inhibiting proline biosynthesis enhances sensitivity of colorectal cancer cells and hepatocellular carcinoma cells to standard of care chemotherapy agents 5-FU and sorafenib, respectively 86,104 . On the other hand, PRODH has been implicated in cell death induced by p53-inducing DNAdamaging drugs 69 and to contribute to anti-tumor activity of celecoxib 79 and troglitazone, a peroxisome proliferatoractivated receptor γ (PPARγ) agonist that induces apoptosis in several cancers 177 . This information will help prioritize cancers for mechanistic studies and preclinical assessments of new compounds targeting proline enzymes.…”

Targeting the Proline–Glutamine–Asparagine–Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy

“…High Pro levels protect cancer cells from oxidative stress during oncogenesis. Pro has antioxidant activity that suppresses the production of ROS [ 15 , 69 , 70 ]. It has been reported that overexpressing ProDH/Pox reduces cellular Pro levels but increased ROS.…”

PRODH/POX-Dependent Celecoxib-Induced Apoptosis in MCF-7 Breast Cancer

“…The mechanism of the chemopreventive effect of celecoxib is not fully understood. Our previous research shows that this drug modulates proline metabolism in oral squamous cells leading to induction of apoptosis [ 5 ]. Breast cancer is a leading cause of death in women based on GLOBOCAN reports [ 6 ].…”

“…The molecular mechanism of switching the PRODH/POX function between introducing cells into the autophagy or apoptosis needs further investigation. It was reported that cancer cells accumulate proline in higher concentrations than healthy cells providing substrate for PRODH/POX activity [ 5 ].…”