Zeinab Mazloumi
1,2 
, Ali Rafat
3, Khadijeh Dizaji Asl
4, Mohammad Karimipour
5, Dariush Shanehbandi
6, Mehdi Talebi
1, Majid Montazer
7, Ali Akbar Movassaghpour
8, Alireza Dehnad
9, Raheleh Farahzadi
8, Hojjatollah Nozad Charoudeh
8* 1 Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
2 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
3 Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
4 Department of Histopathology and Anatomy, Faculty of Medical Sciences, Tabriz Medical Sciences, Islamic Azad University, Tabriz, Iran
5 Department of Anatomical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
6 Immunology Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
7 Department of Cardiovascular Surgery, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
8 Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
9 Department of Bacterial Disease Research, Razi Vaccine, and Serum Research Institute, AREEO, Tabriz, Iran
Abstract
Introduction: High metastasis, resistance to common treatments, and high mortality rate, has made triple-negative breast cancer (TNBC) to be the most invasive type of breast cancer. High telomerase activity and mitochondrial biogenesis are involved in breast cancer tumorigenesis. The catalytic subunit of telomerase, telomerase reverse transcriptase (hTERT), plays a role in telomere lengthening and extra-biological functions such as gene expression, mitochondria function, and apoptosis. In this study, it has been aimed to evaluate intrinsic-, extrinsic-apoptosis and DNMT3a and TET2 expression following the inhibition of telomerase and mitochondria respiration in TNBC cell lines.
Methods: TNBC cells were treated with IC50 levels of BIBR1532, tigecycline, and also their combination. Then, telomere length, and DNMT3a, TET2, and hTERT expression were evaluated. Finally, apoptosis rate, apoptosis-related proteins, and genes were analyzed.
Results: The present results showed that IC50 level of telomerase and inhibition of mitochondria respiration induced apoptosis but did not leave any significant effect on telomere length. The results also indicated that telomerase inhibition induced extrinsic-apoptosis in MDA-MB-231 and caused intrinsic- apoptosis in MDA-MB-468 cells. Furthermore, it was found that the expression of p53 decreased and was ineffective in cell apoptosis. The expressions of DNMT3a and TET2 increased in cells. In addition, combination treatment was better than BIBR1532 and tigecycline alone.
Conclusion: The inhibition of telomerase and mitochondria respiration caused intrinsic- and extrinsic- apoptosis and increased DNMT3a and TET2 expression and it could be utilized in breast cancer treatment.