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

Journal of Experimental & Clinical Cancer Research

See-Hyoung Park¹  Byung-Hyun Park²  Su Jin Ahn²  Young Jae Moon²  Zhongkai Zhang³  Jung Ryul Kim³  Yiping Song³  Sang-A Lee⁴  Ae-Ri Ahn⁴  Sang Hoon Ha⁵  Kyu Yun Jang⁶  Usama Khamis Hussein⁶  Ho Sung Park⁶  Kyoung Min Kim⁶ 

[1] Department of Bio and Chemical Engineering, Hongik University;Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School;Department of Orthopedic Surgery, Jeonbuk National University Medical School;Department of Pathology, Jeonbuk National University Medical School;Division of Biotechnology, Jeonbuk National University;Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital and Research Institute for Endocrine Sciences;

关键词: Osteosarcoma;    SIRT6;    doxorubicin;    apoptosis;    DNA damage;   

DOI  :  10.1186/s13046-020-01759-9

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown