Affiliation:
1. Department of Applied Biology CSIR‐Indian Institute of Chemical Technology Hyderabad India
2. Academy of Scientific and Innovative Research Ghaziabad India
Abstract
AbstractSirtuin 1 (SIRT1), a member of histone deacetylase III family, plays a pivotal role in mediating chemoresistance in several cancers, including breast cancer. However, the molecular mechanism by which the deregulated SIRT1 promotes doxorubicin (Dox) resistance is still elusive. Here, we showed that the cell proliferation rates and invasive properties of MDA‐MB‐231 breast cancer cells were increased from low‐ to high‐Dox‐resistant cells. In agreement, severe combined immunodeficiency disease (SCID) mice bearing labeled MDA‐MB‐231high Dox‐Res cells showed significantly higher tumor growth, angiogenesis, and metastatic ability than parental MDA‐MB‐231 cells. Interestingly, the levels of SIRT1 and glutathione (GSH) were positively correlated with the degree of Dox‐resistance. Dox‐induced SIRT1 promoted NRF2 nuclear translocation with an accompanying increase in the antioxidant response element promotor activity and GSH levels. In contrast, inhibition of SIRT1 by EX527 greatly reversed these events. More so, Dox‐resistance‐induced pro‐proliferative, proangiogenic, and invasive effects were obviated with depletion of either SIRT1 or GSH. Together, Dox‐induced SIRT1 promotes dysregulation of redox homeostasis leading to breast cancer chemoresistance, tumor aggressiveness, angiogenesis, and metastasis.
Reference36 articles.
1. Cancer statistics, 2023;Siegel RL;CA Cancer J Clin,2023
2. Breast cancer statistics, 2022;Giaquinto AN;CA Cancer J Clin,2022
3. Doxorubicin pathways: pharmacodynamics and adverse effects;Thorn CF;Pharmacogenet Genom,2011
4. Mechanisms of doxorubicin‐induced drug resistance and drug resistant tumour growth in a murine breast tumour model;Christowitz C;BMC Cancer,2019
5. Breast cancer: molecular mechanisms of underlying resistance and therapeutic approaches;Tufail M;Am J Cancer Res,2022