Page 62 - SRPSKO DRUŠTVO ISTRAŽIVAČA RAKA

Serbian Association for Cancer Research SDIRSACR

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Manipulation of genes involved in both drug resistance and drug-induced EMT reveals unpredictable
ovarian cancer cell morphology and stress response

Anamaria Brozovic 1

1 Ruđer Bošković Institute, Division of Molecular Biology, Bijenička cesta 54, 10000 Zagreb, Croatia

Keywords: ovarian cancer, drug resistance, metastasis, TMEM200A, PRKAR1B

In the treatment of ovarian cancer (OC), even initially responding patients eventually develop drug resistance. Previously,
TMEM200A and PRKAR1B were recognized as potentially involved in the drug resistance and the metastatic potential
of OC. Furthermore, we have shown that both genes have high predictive and prognostic value for OC patients. The aim
of further work is to investigate the signaling pathways behind the TMEM200A- and PRKAR1B-mediated regulation of
the above-mentioned phenomena. For this purpose, OC cells with stable overexpression of TMEM200A or PRKAR1B
products as well as cells with knock-out of TMEM200A and PRKAR1B were established and characterized. The data
obtained so far show that the influence on drug resistance and metastatic potential mediated by TMEM200A and
PRKAR1B depends on their expression level in the cell and the origin of the cell line. Further work on newly established
research models is needed to understand how TMEM200A and PRKAR1B are involved in drug resistance and drug-
induced metastatic potential of OC.

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Repurposing antidiabetic drugs as a therapeutic approach for breast cancer

Nevena Gajovic , Ivan Jovanovic , Milena Jurisevic , Marina Jovanovic , Andjela Petrovic , Isidora Stanisavljevic ,
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Danijela Maksimovic Ivanic , Sanja Mijatovic , Milan Jovanovic 3
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1Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia
2Department of Immunology, Institute for Biological Research "Siniša Stanković"- National Institute of the Republic of Serbia,
University of Belgrade,Serbia.
3Medical Faculty of Military Medical Academy, University of Defense, Belgrade, Serbia
Keywords: breast cancer, antitumor immune response, antidiabetic drugs, metformin, semaglutide
Background: Breast cancer is the second most frequent type of malignancy in the female population with more than
2.3 million cases and 666,000 deaths in 2022. Triple-negative breast cancer occurs in about 12%-17% of all breast
cancer patients with tendency for early recurrence and fast progression, leading to metastasis in distant organs. Given
the fact that diabetes and cancer share several metabolic pathways, drug repurposing is shedding light on the use of
antidiabetic drugs against various types of cancers. Our main goal was to examine how antidiabetic drugs, metformin
and semaglutide, affect breast cancer growth and antitumor immune response.
Material and Methods: BALB/C wild type female mice were injected with 4T1 breast cancer cells and subsequently
treated with metformin and semaglutide.
Results: Metformin delayed tumor growth via stimulation of function of NK, NKT cells and T cells and inhibition of Tregs
and MDSCs. Metformin administration significantly increased the expression of immunostimulatory miRNA-150 and
miRNA-155, while it decreased the expression of immunosuppressive miRNA-146a in isolated NK cells. Semaglutide
application slowed down tumor appearance, growth and progression. In comparison to metformin, semaglutide
promoted antitumor immune response in non-NK cell way, by increasing accumulation of CD11c+ dendritic cells, while
decreasing Tregs in spleen and primary tumor. Furthermore, semaglutide enhanced the cytotoxic capacity of CD8+ T
cells in vitro.
Conclusion: Metformin and semaglutide target different components of antitumor immune response thereby efficiently
reducing breast cancer growth.

Acknowledgments and funding: This work was supported by a grant from the Serbian Ministry of Education, Science
and Technological Development (175069), a joint project with PR China (06/2018), from the Faculty of Medical Sciences

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