Telomerase and mitochondria inhibition promote apoptosis and TET۲ and DNMT۳a expression in triple negative breast cancer cell lines

High metastasis, resistance to common treatments, and high mortality rate, have made triple-negative breast cancer (TNBC) to be the most invasive type of breast cancer. TNBC is an invasive subtype of breast cancer (containing ۱۵–۲۰%) that does not express Her-۲, Estrogen, and Progesterone receptors. TNBC cells have cancer stem cells’ (CSCs’) origin with less differentiated properties and high proliferation levels. TNBC patients are resistant to conventional therapy and display higher metastasis, disease recurrence, and mortality rates than other subtypes of breast cancer. According to the studies, telomerase activity is high in over ۹۰% of breast cancers. 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. This study has been aimed to evaluate intrinsic-, and extrinsic-apoptosis and DNMT۳a and TET۲ expression following the inhibition of telomerase and mitochondria respiration in TNBC cell lines. Methods: The TNBC cells were treated with IC۵۰ levels of BIBR۱۵۳۲, tigecycline, and their combination. Then, telomere length, and DNMT۳a, TET۲, and hTERT expression were evaluated. Finally, apoptosis rate, apoptosis-related proteins, and genes were analyzed. Results: The present results showed that IC۵۰ 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-۲۳۱ and caused intrinsic- apoptosis in MDA-MB-۴۶۸ cells. Furthermore, it was found that the expression of p۵۳ decreased and was ineffective in cell apoptosis. The expressions of DNMT۳a and TET۲ increased in cells. In addition, combination treatment was better than BIBR۱۵۳۲ and tigecycline alone. Conclusion: The inhibition of telomerase and mitochondria respiration caused intrinsic- and extrinsic- apoptosis and increased DNMT۳a and TET۲ expression and it could be utilized in breast cancer treatment.

کلیدواژه ها:

Cancer stem cell ، Telomerase ، Mitochondria ، DNMT۳a ، TET۲