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抑制SIRT6通过抑制骨肉瘤中的DNA损伤修复途径增强阿霉素的抗肿瘤作用。

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

作者信息

Zhang Zhongkai, Ha Sang Hoon, Moon Young Jae, Hussein Usama Khamis, Song Yiping, Kim Kyoung Min, Park See-Hyoung, Park Ho Sung, Park Byung-Hyun, Ahn Ae-Ri, Lee Sang-A, Ahn Su Jin, Kim Jung Ryul, Jang Kyu Yun

机构信息

Department of Orthopedic Surgery, Jeonbuk National University Medical School, Jeonju, Republic of Korea.

Division of Biotechnology, Jeonbuk National University, Iksan, Republic of Korea.

出版信息

J Exp Clin Cancer Res. 2020 Nov 17;39(1):247. doi: 10.1186/s13046-020-01759-9.

DOI:10.1186/s13046-020-01759-9
PMID:33198792
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7670730/
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.

摘要

背景

SIRT6在细胞中具有多种作用，其在肿瘤发生中的作用存在争议。鉴于SIRT6作为DNA损伤修复诱导剂的作用，它可能参与了抗癌治疗的耐药性。

方法

我们评估了SIRT6在37例骨肉瘤中的预后意义，并研究了SIRT6对阿霉素、奥拉帕尼和ATM抑制剂抗癌作用的治疗效果。

结果

SIRT6的免疫组化表达与骨肉瘤患者较短的总生存期和无复发生存期显著相关，尤其是在接受辅助化疗的患者中。在U2OS和KHOS/NP骨肉瘤细胞中，敲低SIRT6显著增强了阿霉素的凋亡作用，而SIRT6过表达诱导了对阿霉素的耐药性。此外，SIRT6诱导了DNA损伤修复途径，用奥拉帕尼和ATM抑制剂阻断DNA损伤修复途径可减弱SIRT6介导的对阿霉素的耐药性。

结论

本研究表明，抑制SIRT6联合阿霉素可能是治疗骨肉瘤患者的有效方式，特别是对于SIRT6高表达且生存期较短的骨肉瘤患者。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/a98cd15de0d9/13046_2020_1759_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/3c6ff55857be/13046_2020_1759_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/fa342348f8f1/13046_2020_1759_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/5e6e42cc4dac/13046_2020_1759_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/d5a42e61939f/13046_2020_1759_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/95355b807ca0/13046_2020_1759_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/661a20c00a82/13046_2020_1759_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/80da15cfc848/13046_2020_1759_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/a98cd15de0d9/13046_2020_1759_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/3c6ff55857be/13046_2020_1759_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/fa342348f8f1/13046_2020_1759_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/5e6e42cc4dac/13046_2020_1759_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/d5a42e61939f/13046_2020_1759_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/95355b807ca0/13046_2020_1759_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/661a20c00a82/13046_2020_1759_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/80da15cfc848/13046_2020_1759_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a081/7670730/a98cd15de0d9/13046_2020_1759_Fig8_HTML.jpg

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