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Desislava Ivanova, Pantelis Dimaras, Oskan Tasinov, Yoana Kiselova-Kaneva, Maria Tzaneva, Nadezhda Stefanova, Diana Ivanova


In recent years, there has been an expanding interest in understanding metabolic regulation in cancer cells. Since cancer cells are characterized by accelerated rate of proliferation, their metabolic demands are increased. The latter forces cancer cells to facilitate metabolic pathways, which are not normally active in healthy cells. Cancer cells comprising a tumor belong to two major metabolic groups: a) the glucose-dependent cells and b) the lactate-utilizing tumor cells. Taken into consideration the unorganized vasculature and shunts creating this regional hypoxia, tumor cells develop symbiotic metabolic behavior to utilize the lactate produced through aerobic glycolysis (Warburg effect) and anaerobic glycolysis (Pasteur effect). Our focus was on three regulatory genes SIRT6, FOXO4, HIF3A, which orchestrate basic metabolic pathways, such as energy metabolism, and regulate proliferation. Their expression is altered in conjunction with cancer type and stage. Our results of RAS mutant colorectal cancer (CRC) patients showed only slight increase of HIF3A level, whereas in RAS wild type (wt) patients all of the investigated genes have increased their expression, when the results are normalized against RPL37A endogenous control. By comparing the mutant with wt patients, we identified increased expression of all three protein-coding genes in the mutant and decreased levels in all of them in wt patients. When comparing the gene expression in the different stages of cancer progression, we detected decreased levels of SIRT6 in the earlier stages and increased levels of SIRT6 in the later stages of CRC. SIRT6 functions as an ADP-ribosylase and NAD+- dependent deacetylase and is able to regulate DNA repair, telomere maintenance and glucose and lipid metabolism, therefore affecting metabolic and age-related diseases, such as cancer. Our results are in agreement with the fact that the high levels of SIRT6 in later stages of CRC lead to survival of the cancer cells by decreasing the accumulation rate of mutations. FOXO is decreased at first, then is upregulated in the middle stage and in later stages it doesn’t show any significant change in its gene expression levels. FOXO4 functions as tumor suppressor by inhibiting cell proliferation, inducing apoptosis and protecting cells from DNA damage and oxidative stress. HIF3A has increased accumulation rate in the early and middle stages, and later on its levels drop. HIF3A is induced by hypoxia. Overexpression of the related HIF3A increases colorectal cancer tumor growth by activating pro-survival STAT3 signaling pathways. Our analyses showed average correlation between SIRT6 and FOXO4 in RAS mutant patients and between SIRT6 and HIF3A in RAS wt CRC patients. We observed strong correlation between SIRT6 and HIF3A in stage IV of CRC progression. Our results showed an active relationship between the SIRT 6 and both FOXO4 and HIF3A, which is in agreement with the earlier suggested interactions between all these protein coding genes.

Acknowledgement: Medical University of Varna (2016), Fund “Science” project No 16020, supported the experiments done on this study



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About The Authors

Desislava Ivanova

Pantelis Dimaras

Oskan Tasinov

Yoana Kiselova-Kaneva

Maria Tzaneva

Nadezhda Stefanova

Diana Ivanova

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