Background and Purpose: Although limited by side effects and development of resistance, doxorubicin still represent the most common chemotherapy for breast cancer. Thus, the identification of critical molecules to alleviate doxorubicin resistance is crucial. Here, we provide a molecular rationale for the breast cancer patients potentially benefitting from doxorubicin based on the expression levels of SIRT1, a identified member of longevity genes.
Methods: SIRT1-overexpressed and SIRT1-knockdown breast cancer cells were established to investigate the functions of SIRT1 in regulating doxorubicin resistance both in vitro and in vivo. Cell proliferation was analyzed via CCK8 assay, cell apoptosis was studied by TUNEL anslysis. Molecule interaction was analyzed through co-immunoprecipitation and immunofluorescence techniques. Sensibility to doxorubicin was assessed in vivo through nude mice tumorigenicity experiment.
Results: First, SIRT1 was found higher-expressed in breast cancer doxorubicin-resistant cells MCF-7/ADR than that in doxorubicin- sensitive cells MCF-7. Moreover, SIRT1-knockdown MCF-7/ADR cells showed higher susceptible to doxorubicin both in vitro and in vivo models, whereas overexpressing of SIRT1 obviously inhibited this phenotype. Accordingly, SIRT1 was found interacted with Akt, consequently promoted the activity of Akt in MCF-7/ADR cells in vitro and positively correlated with the expression of P-Akt in vivo. Reversion the activity of Akt partially downturned the doxorubicin-resistant effects mediated by SIRT1.
Conclusion: This investigation suggested the value of SIRT1 as biomarker of response to doxorubicin, leading to the development of new tools for the management of breast cancer patients.