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.

Download Full-text

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 ◽

10.1186/s13046-020-01759-9 ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Zhongkai Zhang ◽

Sang Hoon Ha ◽

Young Jae Moon ◽

Usama Khamis Hussein ◽

Yiping Song ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Repair ◽

Prognostic Significance ◽

Repair Pathway ◽

Anticancer Effects ◽

Damage Repair ◽

Anti Cancer ◽

Resistance To Doxorubicin ◽

Apoptotic Effects

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.

Download Full-text

CK2α/CSNK2A1 Induces Resistance to Doxorubicin Through SIRT6 Mediated Activation of the DNA Damage Repair Pathway

10.21203/rs.3.rs-624074/v1 ◽

2021 ◽

Author(s):

Usama Khamis Hussein ◽

Asmaa Gamal Ahmed ◽

Yiping Song ◽

See-Hyoung Park ◽

Kyoung Min Kim ◽

...

Keyword(s):

Dna Damage ◽

Cancer Progression ◽

Dna Damage Repair ◽

Repair Pathway ◽

Osteosarcoma Cells ◽

Cytotoxic Effects ◽

Damage Repair ◽

Anti Cancer ◽

Resistance To Doxorubicin

Abstract BackgroundCK2α/CSNK2A1 is involved in cancer progression by phosphorylating various signaling molecules. Considering the role of CSNK2A1 in cancer progression and phosphorylation of SIRT6 and the role of SIRT6 in chemoresistance through the DNA damage repair pathway, CSNK2A1 and SIRT6 might be involved in resistance to the conventional anti-cancer therapies.MethodsWe evaluated the expression of CSNK2A1 in the 37 osteosarcoma patients and investigated the effects of CSNK2A1 and phosphorylation of SIRT6 on Ser338 on the resistance to the anti-cancer effects of doxorubicin. Results Higher expression of CSNK2A1 predicted shorter overall survival and relapse-free survival in both general osteosarcoma patients and sub-population of patients who received postoperative chemotherapies. U2OS and KHOS/NP osteosarcoma cells with induced overexpression of CSNK2A1 were resistant to cytotoxic effects of doxorubicin, and knock-down of CSNK2A1 potentiated the cytotoxic effects of doxorubicin. CSNK2A1 overexpression-mediated resistance to doxorubicin was associated with SIRT6 phosphorylation and induction of the DNA damage repair pathway molecules ATM and Chk2. CSNK2A1 and SIRT6 mediated resistance to doxorubicin in vivo was attenuated via mutation of SIRT6 at the Ser338 phosphorylation site. Emodin, a CSNK2A1 inhibitor, potentiated the cytotoxic effects of doxorubicin in osteosarcoma cells in vitro. ConclusionsThis study demonstrates that the expression of CSNK2A1 might be used as a prognostic indicator of osteosarcoma. In addition, it suggests that CSNK2A1 induces resistance to doxorubicin through phosphorylation of SIRT6-mediated activation of the DNA damage repair pathway. Therefore, blocking the CSNK2A1-SIRT6-DNA damage repair pathway might be a new therapeutic stratagem for the poor prognostic subgroup of osteosarcomas with high expression of CSNK2A1.

Download Full-text

CK2α/CSNK2A1 Induces Resistance to Doxorubicin through SIRT6-Mediated Activation of the DNA Damage Repair Pathway

Cells ◽

10.3390/cells10071770 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1770

Author(s):

Usama Khamis Hussein ◽

Asmaa Gamal Ahmed ◽

Yiping Song ◽

Kyoung Min Kim ◽

Young Jae Moon ◽

...

Keyword(s):

Dna Damage ◽

Cancer Progression ◽

Dna Damage Repair ◽

Repair Pathway ◽

Osteosarcoma Cells ◽

Cytotoxic Effects ◽

Damage Repair ◽

Anti Cancer ◽

Resistance To Doxorubicin

CK2α/CSNK2A1 is involved in cancer progression by phosphorylating various signaling molecules. Considering the role of CSNK2A1 in cancer progression and the phosphorylation of SIRT6 and the role of SIRT6 in chemoresistance through the DNA damage repair pathway, CSNK2A1 and SIRT6 might be involved in resistance to conventional anti-cancer therapies. We evaluated the expression of CSNK2A1 and phosphorylated SIRT6 in the 37 osteosarcoma patients and investigated the effects of CSNK2A1 and the phosphorylation of SIRT6 on Ser338 on resistance to the anti-cancer effects of doxorubicin. Higher expression of CSNK2A1 and phosphorylated SIRT6 was associated with shorter survival in osteosarcoma patients. U2OS and KHOS/NP osteosarcoma cells with induced overexpression of CSNK2A1 were resistant to the cytotoxic effects of doxorubicin, and the knock-down of CSNK2A1 potentiated the cytotoxic effects of doxorubicin. CSNK2A1 overexpression-mediated resistance to doxorubicin was associated with SIRT6 phosphorylation and the induction of the DNA damage repair pathway molecules. CSNK2A1- and SIRT6-mediated resistance to doxorubicin in vivo was attenuated via mutation of SIRT6 at the Ser338 phosphorylation site. Emodin, a CSNK2A1 inhibitor, potentiated the cytotoxic effects of doxorubicin in osteosarcoma cells. This study suggests that blocking the CSNK2A1-SIRT6-DNA damage repair pathway might be a new therapeutic stratagem for osteosarcomas.

Download Full-text

Nbs1‐mediated DNA damage repair pathway regulates haematopoietic stem cell development and embryonic haematopoiesis

Cell Proliferation ◽

10.1111/cpr.12972 ◽

2021 ◽

Author(s):

Yu Chen ◽

Jie Sun ◽

Zhenyu Ju ◽

Zhao‐Qi Wang ◽

Tangliang Li

Keyword(s):

Dna Damage ◽

Stem Cell ◽

Dna Damage Repair ◽

Cell Development ◽

Haematopoietic Stem Cell ◽

Repair Pathway ◽

Damage Repair

Download Full-text

Metabolomics Reveals Aging-associated Attenuation of Noninvasive Radiation Biomarkers in Mice: Potential Role of Polyamine Catabolism and Incoherent DNA Damage-repair

Journal of Proteome Research ◽

10.1021/pr400161k ◽

2013 ◽

Vol 12 (5) ◽

pp. 2269-2281 ◽

Cited By ~ 23

Author(s):

Soumen K. Manna ◽

Kristopher W. Krausz ◽

Jessica A. Bonzo ◽

Jeffrey R. Idle ◽

Frank J. Gonzalez

Keyword(s):

Dna Damage ◽

Potential Role ◽

Dna Damage Repair ◽

Polyamine Catabolism ◽

Damage Repair

Download Full-text

Investigating the Role of SF3B1 Mutations in DNA Damage Repair in Myeloid Malignancies

Leukemia Research ◽

10.1016/s0145-2126(17)30391-0 ◽

2017 ◽

Vol 55 ◽

pp. S159-S160

Author(s):

K. Lappin ◽

F. Liberante ◽

K. Savage ◽

K. Mills

Keyword(s):

Dna Damage ◽

Dna Damage Repair ◽

Myeloid Malignancies ◽

Damage Repair

Download Full-text

The Fanconi anemia DNA damage repair pathway in the spotlight for germline predisposition to colorectal cancer

European Journal of Human Genetics ◽

10.1038/ejhg.2016.44 ◽

2016 ◽

Vol 24 (10) ◽

pp. 1501-1505 ◽

Cited By ~ 25

Author(s):

Clara Esteban-Jurado ◽

◽

Sebastià Franch-Expósito ◽

Jenifer Muñoz ◽

Teresa Ocaña ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Damage ◽

Fanconi Anemia ◽

Dna Damage Repair ◽

Repair Pathway ◽

Damage Repair

Download Full-text

Abstract 2039: The role of HORMAD1 in DNA damage repair in squamous cell carcinomas

10.1158/1538-7445.am2021-2039 ◽

2021 ◽

Author(s):

Jennifer Gantchev ◽

Amelia Martinez Villarreal ◽

Brandon Ramchatesingh ◽

Ivan V. Litvinov

Keyword(s):

Dna Damage ◽

Squamous Cell ◽

Dna Damage Repair ◽

Squamous Cell Carcinomas ◽

Damage Repair

Download Full-text

MicroRNA-146a-5p enhances radiosensitivity in hepatocellular carcinoma through replication protein A3-induced activation of the DNA repair pathway

AJP Cell Physiology ◽

10.1152/ajpcell.00189.2018 ◽

2019 ◽

Vol 316 (3) ◽

pp. C299-C311 ◽

Cited By ~ 12

Author(s):

Jing Luo ◽

Zhong-Zhou Si ◽

Ting Li ◽

Jie-Qun Li ◽

Zhong-Qiang Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Dna Damage ◽

Dna Repair ◽

Dna Damage Repair ◽

Replication Protein ◽

Repair Pathway ◽

Related Factors ◽

Damage Repair ◽

Hcc Cells

Hepatocellular carcinoma (HCC) is known for its high mortality rate worldwide. Based on intensive studies, microRNA (miRNA) expression functions in tumor suppression. Therefore, we aimed to evaluate the contribution of miR-146a-5p to radiosensitivity in HCC through the activation of the DNA damage repair pathway by binding to replication protein A3 (RPA3). First, the limma package of R was performed to differentially analyze HCC expression chip, and regulative miRNA of RPA3 was predicted. Expression of miR-146a-5p, RPA3, and DNA damage repair pathway-related factors in tissues and cells was determined. The effects of radiotherapy on the expression of miR-146a-5p and RPA3 as well as on cell radiosensitivity, proliferation, cell cycle, and apoptosis were also assessed. The results showed that there exists a close correlation between miR-146a and the radiotherapy effect on HCC progression through regulation of RPA3 and the DNA repair pathway. The positive rate of ATM, pCHK2, and Rad51 in HCC tissues was higher when compared with that of the paracancerous tissues. SMMC-7721 and HepG2 cell proliferation were significantly inhibited following 8 Gy 6Mv dose. MiR-146a-5p restrained the expression of RPA3 and promoted the expression of relative genes associated with the DNA repair pathway. In addition, miR-146a-5p overexpression suppresses cell proliferation and enhances radiosensitivity and cell apoptosis in HCC cells. In conclusion, the present study revealed that miR-146a-5p could lead to the restriction of proliferation and the promotion of radiosensitivity and apoptosis in HCC cells through activation of DNA repair pathway and inhibition of RPA3.

Download Full-text