Serine metabolism, curcumin and cancer cells response to cisplatin in vitro
Metabolic reprogramming of a cancer cell depends on environmental factors, the genetic background and the cell's lineage of origin. Three enzymes are directly involved in serine synthesis de novo: 3-phosphoglycerate dehydrogenase (PHGDH); phosphoserine aminotransferase (PSAT1); and phosphoserine phosphatase (PSPH). The activity of this pathway enables the cancer cell to create biomass, nucleotides and glutathione. The coenzyme NAD+ is necessary for the activity of PHGDH. The activity of PSAT1 leads to the formation of alpha-ketoglutarate, which is needed for activity of numerous histone lysine-demethylases and TET DNA demethylases. Curcumin sensitizes cancer cells response to chemotherapeutic agents. We showed that curcumin increases both, PHGDH mRNA and protein, in cells originating from malignant head and neck tumors. The latest literature data indicate an increased sensitivity to cisplatin in ovarian tumors with increased PHGDH activity. We propose to investigate the modulation of transcription, synthesis and localization of key proteins relating to the serine biosynthetic pathway, in curcumin or/and cisplatin exposed cancer cells originating from head and neck tumors and colon tumors. We plan to use functional cellular analyses, measure the level of amino acids and apply appropriate molecular genetic methods. The importance of phenomena obtained will be estimated through: a) measurement of cellular proliferation and viability in vitro; b) selective silencing of critical hubs of the network b) monitoring response to treatment with respect to expression of selected enzymes, in the clinical samples. The key network regulators were determined: a) based on the results of the completed HRZZ project; b) preliminary results and c) using the TCGA database and publicly available software. A diet low in serine is increasingly being investigated in approaches to cancer treatment, the obtained results will significantly improve knowledge in this field of molecular oncology.