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

Abstract

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.

Acetylshikonin, A Novel CYP2J2 Inhibitor, Induces Apoptosis in RCC Cells via FOXO3 Activation and ROS Elevation

“…Primary antibodies were diluted to 1 : 500~1000 ratio, and secondary antibodies were diluted to 1 : 5000 ratio for use. All the experimental protocols were referred from our previous publications [ 13 , 45 , 46 ].…”

Expression Patterns of PAK4 and PHF8 Are Associated with the Survival of Gallbladder Carcinoma Patients

“…The tissue sections were incubated with primary antibodies for PAK4 (Cat# 14685-1-AP, 1:100, Proteintech, Chicago, IL, USA) and PHF8 (Cat# IHC-00343, 1:100, Bethyl Laboratories, Montgomery, TX, USA) and then visualized using the DAKO Envision system (DAKO, Carpinteria, CA, USA). Slides that underwent immune staining of PAK4 and PHF8 were evaluated based on the intensity and extent of the staining in the cytoplasm or nuclei of tumor cells [ 30 , 31 , 32 ]. The staining intensity and area were rated on scales of 0 to 3 (0; no staining, 1; weak, 2; intermediate, 3; strong) and 0 to 5 (0; 0%, 1; 1%, 2; 2–10%, 3; 11–33%, 4; 34–66%, 5; 67–100%), respectively [ 30 , 31 , 32 ].…”

“…Slides that underwent immune staining of PAK4 and PHF8 were evaluated based on the intensity and extent of the staining in the cytoplasm or nuclei of tumor cells [ 30 , 31 , 32 ]. The staining intensity and area were rated on scales of 0 to 3 (0; no staining, 1; weak, 2; intermediate, 3; strong) and 0 to 5 (0; 0%, 1; 1%, 2; 2–10%, 3; 11–33%, 4; 34–66%, 5; 67–100%), respectively [ 30 , 31 , 32 ]. The final immunohistochemical score was obtained by adding the staining intensity and area scores for each of the two TMA cores, resulting in a score ranging from zero to sixteen.…”