MST-312 Alters Telomere Dynamics, Gene Expression Profiles and Growth in Human Breast Cancer Cells

作者：Gurung Resham Lal; Lim Shi Ni; Low Grace Kah Mun; Hande M Prakash^*

来源：Journal of Nutrigenetics and Nutrigenomics, 2014, 7(4-6): 283-298.

DOI：10.1159/000381346

• DNA damage/repair
• Telomeres
• Telomerase
• Cancer chemotherapy

Background: Targeting telomerase is a potential cancer management strategy given that it allows unlimited cellular replication in the majority of cancers. Dysfunctional telomeres are recognized as double-strand breaks. However, the status of DNA repair response pathways following telomerase inhibition is not well understood in human breast cancer cells. Here, we evaluated the effects of MST-312, a chemically modified derivative from tea catechin, epigallocatechin gallate, on telomere dynamics and DNA damage gene expression in breast cancer cells. Methodology: Breast cancer cells MCF-7 and MDA-MB-231 were treated with MST-312, and telomere-telomerase homeostasis, induced DNA damage and gene expression profiling were analyzed. Results: MST-312 decreased telomerase activity and induced telomere dysfunction and growth arrest in breast cancer cells with more profound effects in MDA-MB-231 than in MCF-7 cells. Consistent with these data, the telomere-protective protein TRF2 was downregulated in MDA-MB-231 cells. MST-312 induced DNA damage at telomeres accompanied by reduced expression of DNA damage-related genes ATM and RAD50. Co-treatment with MST-312 and the poly(ADP-ribose) polymerase 1 (PARP-1) inhibitor PJ-34 further enhanced growth reduction as compared to single treatment with MST-312 or PJ-34. Conclusions: Our work demonstrates potential importance for the establishment of antitelomerase cancer therapy using MST-312 along with PARP-1 inhibition in breast cancer therapy.

• 出版日期2014