Inhibition of SIRT6 potentiates the anti-tumor effect of doxorubicin through suppression of the DNA damage repair pathway in osteosarcoma

Abstract

Background SIRT6 has diverse roles in cells, and the role of SIRT6 in tumorigenesis is controversial. Considering the role of SIRT6 as an inducer of DNA damage repair, it might be involved in resistance to anti-cancer therapy. Methods We evaluated the prognostic significance of SIRT6 in 37 osteosarcomas and investigated the therapeutic efficacy of SIRT6 on the anticancer effects of doxorubicin, olaparib, and ATM inhibitor. Results Immunohistochemical expression of SIRT6 was significantly associated with shorter overall survival and relapse-free survival of osteosarcoma patients, especially in patients who received adjuvant chemotherapy. In U2OS and KHOS/NP osteosarcoma cells, knock-down of SIRT6 significantly potentiated apoptotic effects of doxorubicin and SIRT6 overexpression induced resistance to doxorubicin. Moreover, SIRT6 induced the DNA damage repair pathway and SIRT6-mediated resistance to doxorubicin was attenuated by blocking the DNA damage repair pathway with olaparib and ATM inhibitor. Conclusions This study suggests that suppression of SIRT6 in combination with doxorubicin might be an effective modality in the treatment of osteosarcoma patients, especially for osteosarcomas with shorter survival with high expression of SIRT6.

SCRIB Is Involved in the Progression of Ovarian Carcinomas in Association with the Factors Linked to Epithelial-to-Mesenchymal Transition and Predicts Shorter Survival of Diagnosed Patients

“…Next, 2 × 10 6 SKOV3 cells were transfected with the indicated vectors via subcutaneous injection into the flank after mixing with Corning matrigel Basement Membrane Matrix (1:1) (Catalog #; 356234, Bedford, MA, USA). Tumor size was measured every week and calculated by the following equation: tumor volume = length × width × height × 0.52 [ 10 , 22 , 24 ]. The mice were euthanized according to humane end points at six weeks after tumor cell inoculation.…”

“…The scoring of immunostained slides was conducted according to the Allred scoring system [20]. The Allred scoring system utilizes a staining intensity score (0; no staining, 1; weak, 2; intermediate, 3; strong) and a staining area score (0; no staining, 1; 1%, 2; 2-10%, 3: 11-33%, 4; 34-66%, 5; 67-100%) [20][21][22]. The final scores were obtained by adding the staining intensity score and staining area score.…”

The Two-Faced Role of SIRT6 in Cancer

“…The tumor promoting role of SIRT6 has also been investigated in other cancer types, where reduction of SIRT6 levels is associated to a better response to chemotherapeutics [ 84 , 85 , 95 ]. In metastatic prostate cancer cell lines, SIRT6 knockdown improves chemotherapy sensitivity, with increased DNA damage and consequent cell cycle arrest in G1 along with Bcl-2 downregulation and apoptosis induction [ 84 ].…”

“…SIRT6 also antagonizes the activity of the tumor suppressors p53 and FoxO3a both directly via deacetylation, and indirectly through suppression of their expression [ 85 ]. In osteosarcoma cell lines, SIRT6 knock-down has been shown to potentiate the effect of conventional chemotherapeutics inducing block of cancer cell proliferation and cell death [ 95 ]. SIRT6 inhibition, together with the action of doxorubicin, results in an increase of apoptotic response with a higher expression of Bax and cleaved forms of PARP1 and caspase-3, along with the downregulation of Bcl2 [ 95 ].…”

Mono(ADP-ribosyl)ation Enzymes and NAD+ Metabolism: A Focus on Diseases and Therapeutic Perspectives

“…Inhibition of SIRT6 by OSS-128167 blocked the expression of thermogenic genes and activation of white fat breakdown, showing that SIRT6/AMPK pathway increase energy consumption, insulin sensitivity and heat production, thereby alleviating metabolic disorders [ 183 ]. Treatment of osteosarcoma with SIRT6 inhibitors increased sensitivity to doxorubicin through increased damaged DNA [ 184 ]. Finally, the development of small molecules inhibiting specifically either deacetylation or MARylation may provide new clues on SIRT6 functions [ 185 ].…”