TY  - CONF
AU  - Markelić, Milica
AU  - Otašević, Vesna
AU  - Gudelj, Anđelija
AU  - Saksida, Tamara
AU  - Stančić, Ana
AU  - Veličković, Ksenija
AU  - Krstić, Jelena
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6404
AB  - Recently, it has been suggested that nutrient deprivation (ND) may be effective as an adjuvant 
therapy to hepatocellular carcinoma (HCC) cell treatment with sorafenib (Sfb)1. These results 
suggest that ND-mediated priming of HCC cells to Sfb is positively correlated with the p53 status, 
suggesting the essential role of p53 in priming of HCC cells for regulated cell death (RCD). 
Preliminary data indicated morphological signs of ferroptotic RCD, so we aimed to determine whether 
ferroptosis plays a role in the removal of HCC cells in vitro with respect to their p53 status. To 
this end, p53 wild-type (p53WT) and p53 knockout (p53KO) HepG2 cells were grown in growth medium or 
in starvation medium and treated with Sfb or with ferroptosis inducer, Rsl- 3, for 6 h. 
Morphological signs of RCD and nuclear translocation (i.e. activation) of Nrf2, (master regulator 
of ferroptosis-related signalling pathways), as well as protein levels of antioxidative defence 
(AD) enzymes (CAT, CuZnSOD, MnSOD) and ferroptosis-related proteins (GPX4, xCT) were analysed. The 
AD response to Rsl-3 treatment in p53WT cells was similar regardless of nutritional status, as the 
level of all analysed enzymes increased. The response to Sfb was enhanced by ND as CAT and CuZnSOD 
were elevated. p53KO cells responded quite differently, even when treated with Rsl-3, increasing 
only MnSOD. Starved Sfb-treated p53KO cells even decreased expression of AD enzymes. All signs of a 
proferroptotic response examined were present in starved p53WT cells (regardless of treatment): 
decreased nuclear translocation of Nrf2, GPX4, and xCT expression. Nrf2 activation and GPX4 
expression were also decreased in starved p53KO cells (especially upon treatment with Sfb or 
Rsl-3), but accompanied by compensatory overexpressed xCT. These results may be indicative of 
enhanced AD in p53KO cells and may therefore explain, at least in part, their resistance to 
treatment with Sfb+ND which, as presented here, induces ferroptosis in p53WT HepG2 cells.
PB  - Belgrade: Faculty of Chemistry
C3  - Biochemistry in Biotechnology: Serbian Biochemical Society, Twelfth Conference, International scientific meeting; 2023 Sep 21-23; Belgrade, Serbia
T1  - Proferroptotic response to nutrient deprivation in hepatocellular carcinoma cells is related to p53 status
SP  - 86
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6404
ER  - 

@conference{
author = "Markelić, Milica and Otašević, Vesna and Gudelj, Anđelija and Saksida, Tamara and Stančić, Ana and Veličković, Ksenija and Krstić, Jelena",
year = "2023",
abstract = "Recently, it has been suggested that nutrient deprivation (ND) may be effective as an adjuvant 
therapy to hepatocellular carcinoma (HCC) cell treatment with sorafenib (Sfb)1. These results 
suggest that ND-mediated priming of HCC cells to Sfb is positively correlated with the p53 status, 
suggesting the essential role of p53 in priming of HCC cells for regulated cell death (RCD). 
Preliminary data indicated morphological signs of ferroptotic RCD, so we aimed to determine whether 
ferroptosis plays a role in the removal of HCC cells in vitro with respect to their p53 status. To 
this end, p53 wild-type (p53WT) and p53 knockout (p53KO) HepG2 cells were grown in growth medium or 
in starvation medium and treated with Sfb or with ferroptosis inducer, Rsl- 3, for 6 h. 
Morphological signs of RCD and nuclear translocation (i.e. activation) of Nrf2, (master regulator 
of ferroptosis-related signalling pathways), as well as protein levels of antioxidative defence 
(AD) enzymes (CAT, CuZnSOD, MnSOD) and ferroptosis-related proteins (GPX4, xCT) were analysed. The 
AD response to Rsl-3 treatment in p53WT cells was similar regardless of nutritional status, as the 
level of all analysed enzymes increased. The response to Sfb was enhanced by ND as CAT and CuZnSOD 
were elevated. p53KO cells responded quite differently, even when treated with Rsl-3, increasing 
only MnSOD. Starved Sfb-treated p53KO cells even decreased expression of AD enzymes. All signs of a 
proferroptotic response examined were present in starved p53WT cells (regardless of treatment): 
decreased nuclear translocation of Nrf2, GPX4, and xCT expression. Nrf2 activation and GPX4 
expression were also decreased in starved p53KO cells (especially upon treatment with Sfb or 
Rsl-3), but accompanied by compensatory overexpressed xCT. These results may be indicative of 
enhanced AD in p53KO cells and may therefore explain, at least in part, their resistance to 
treatment with Sfb+ND which, as presented here, induces ferroptosis in p53WT HepG2 cells.",
publisher = "Belgrade: Faculty of Chemistry",
journal = "Biochemistry in Biotechnology: Serbian Biochemical Society, Twelfth Conference, International scientific meeting; 2023 Sep 21-23; Belgrade, Serbia",
title = "Proferroptotic response to nutrient deprivation in hepatocellular carcinoma cells is related to p53 status",
pages = "86",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6404"
}

Markelić, M., Otašević, V., Gudelj, A., Saksida, T., Stančić, A., Veličković, K.,& Krstić, J.. (2023). Proferroptotic response to nutrient deprivation in hepatocellular carcinoma cells is related to p53 status. in Biochemistry in Biotechnology: Serbian Biochemical Society, Twelfth Conference, International scientific meeting; 2023 Sep 21-23; Belgrade, Serbia
Belgrade: Faculty of Chemistry., 86.
https://hdl.handle.net/21.15107/rcub_ibiss_6404

Markelić M, Otašević V, Gudelj A, Saksida T, Stančić A, Veličković K, Krstić J. Proferroptotic response to nutrient deprivation in hepatocellular carcinoma cells is related to p53 status. in Biochemistry in Biotechnology: Serbian Biochemical Society, Twelfth Conference, International scientific meeting; 2023 Sep 21-23; Belgrade, Serbia. 2023;:86.
https://hdl.handle.net/21.15107/rcub_ibiss_6404 .

Markelić, Milica, Otašević, Vesna, Gudelj, Anđelija, Saksida, Tamara, Stančić, Ana, Veličković, Ksenija, Krstić, Jelena, "Proferroptotic response to nutrient deprivation in hepatocellular carcinoma cells is related to p53 status" in Biochemistry in Biotechnology: Serbian Biochemical Society, Twelfth Conference, International scientific meeting; 2023 Sep 21-23; Belgrade, Serbia (2023):86,
https://hdl.handle.net/21.15107/rcub_ibiss_6404 .

TY  - JOUR
AU  - Hmaid, Amal AAA
AU  - Markelić, Milica
AU  - Otašević, Vesna
AU  - Mašović, Sava
AU  - Janković, Aleksandra
AU  - Korać, Bato
AU  - Korać, Aleksandra
PY  - 2016
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6212
AB  - Structural changes affecting cardiomyocyte function may contribute to the pathophysiological remodeling underlying cardiac function impairment. Recent reports have shown that endogenous nitric oxide (NO) plays an important role in this process. In order to examine the role of NO in cardiomyocyte remodeling, male rats were acclimated to room temperature (22 ± 1 °C) or cold (4 ± 1 °C) and treated with 2.25% l-arginine·HCl or 0.01% l-NAME (Nω-nitro-l-arginine methyl ester)·HCl for 45 days. Untreated groups served as controls. Right heart ventricles were routinely prepared for light microscopic examination. Stereological estimations of volume densities of cardiomyocytes, surrounding blood vessels and connective tissue, as well as the morphometric measurements of cardiomyocyte diameters were performed. Tissue sections were also analyzed for structural alterations. We observed that both l-arginine and l-NAME supplementation induced cardiomyocyte hypertrophy, regardless of ambient temperature. However, cardiomyocyte hypertrophy was associated with fibrosis and extra collagen deposition only in the l-NAME treated group. Taken together, our results suggest that NO has a modulatory role in right heart ventricle remodeling by coordinating hypertrophy of cardiomyocytes and fibrous tissue preventing cardiac fibrosis.
PB  - Elsevier
T2  - Saudi Journal of Biological Sciences
T1  - Structural alterations in rat myocardium induced by chronic l-arginine and l-NAME supplementation
IS  - 3
VL  - 25
DO  - 10.1016/j.sjbs.2016.01.022
SP  - 537
EP  - 544
ER  - 

@article{
author = "Hmaid, Amal AAA and Markelić, Milica and Otašević, Vesna and Mašović, Sava and Janković, Aleksandra and Korać, Bato and Korać, Aleksandra",
year = "2016",
abstract = "Structural changes affecting cardiomyocyte function may contribute to the pathophysiological remodeling underlying cardiac function impairment. Recent reports have shown that endogenous nitric oxide (NO) plays an important role in this process. In order to examine the role of NO in cardiomyocyte remodeling, male rats were acclimated to room temperature (22 ± 1 °C) or cold (4 ± 1 °C) and treated with 2.25% l-arginine·HCl or 0.01% l-NAME (Nω-nitro-l-arginine methyl ester)·HCl for 45 days. Untreated groups served as controls. Right heart ventricles were routinely prepared for light microscopic examination. Stereological estimations of volume densities of cardiomyocytes, surrounding blood vessels and connective tissue, as well as the morphometric measurements of cardiomyocyte diameters were performed. Tissue sections were also analyzed for structural alterations. We observed that both l-arginine and l-NAME supplementation induced cardiomyocyte hypertrophy, regardless of ambient temperature. However, cardiomyocyte hypertrophy was associated with fibrosis and extra collagen deposition only in the l-NAME treated group. Taken together, our results suggest that NO has a modulatory role in right heart ventricle remodeling by coordinating hypertrophy of cardiomyocytes and fibrous tissue preventing cardiac fibrosis.",
publisher = "Elsevier",
journal = "Saudi Journal of Biological Sciences",
title = "Structural alterations in rat myocardium induced by chronic l-arginine and l-NAME supplementation",
number = "3",
volume = "25",
doi = "10.1016/j.sjbs.2016.01.022",
pages = "537-544"
}

Hmaid, A. A., Markelić, M., Otašević, V., Mašović, S., Janković, A., Korać, B.,& Korać, A.. (2016). Structural alterations in rat myocardium induced by chronic l-arginine and l-NAME supplementation. in Saudi Journal of Biological Sciences
Elsevier., 25(3), 537-544.
https://doi.org/10.1016/j.sjbs.2016.01.022

Hmaid AA, Markelić M, Otašević V, Mašović S, Janković A, Korać B, Korać A. Structural alterations in rat myocardium induced by chronic l-arginine and l-NAME supplementation. in Saudi Journal of Biological Sciences. 2016;25(3):537-544.
doi:10.1016/j.sjbs.2016.01.022 .

Hmaid, Amal AAA, Markelić, Milica, Otašević, Vesna, Mašović, Sava, Janković, Aleksandra, Korać, Bato, Korać, Aleksandra, "Structural alterations in rat myocardium induced by chronic l-arginine and l-NAME supplementation" in Saudi Journal of Biological Sciences, 25, no. 3 (2016):537-544,
https://doi.org/10.1016/j.sjbs.2016.01.022 . .