Objectives:Our previous research demonstrated that SIC-19,an innovative inhibitor of salt-inducible kinase 2(SIK2),effectively reduces SIK2 protein levels through the ubiquitin-proteasome pathway and exhibits syntheti...Objectives:Our previous research demonstrated that SIC-19,an innovative inhibitor of salt-inducible kinase 2(SIK2),effectively reduces SIK2 protein levels through the ubiquitin-proteasome pathway and exhibits synthetic lethal effects with poly ADP-ribose polymerase(PARP)inhibitors in ovarian cancer.However,the role of SIC-19 in triplenegative breast cancer(TNBC)and pancreatic cancer(PC)remains poorly defined.This study aims to investigate whether SIC-19 combined with PARP inhibitors can induce synthetic lethal effects in TNBC and PC.Methods:Cell lines with high SIK2 expression were identified through Western blot analysis.The combination’s impact was evaluated using Cell Counting Kit-8(CCK8),clone formation,and apoptosis assays,as well as in vivo xenograft models.Results:Our findings indicated that the IC50 of SIC-19 was inversely correlated with endogenous SIK2 expression in TNBC and PC cell lines.SIC-19 modulates the homologous recombination repair pathway by suppressing levels of RAD50-pS635,thereby enhancing the sensitivity of TNBC and PC cells,as well as xenografts,to PARP inhibitors.Conclusion:These results underscore the potential of combining PARP inhibitors in combination with SIK2 inhibitors as a novel therapeutic approach to increase PARP inhibition’s effectiveness in treating TNBC and PC.This innovative combination therapy represents a promising approach for overcoming resistance mechanisms and improving the outcomes for patients with these challenging malignancies.展开更多
目的探究盐诱导激酶2(SIK2)对大鼠心脏缺血再灌注损伤的影响及机制。方法建立大鼠心肌缺血再灌注损伤模型,随机分为假手术组、缺血再灌注组、SIK2抑制剂组,5只/组(造模前24 h左股静脉注射博舒替尼10 mg/kg)。超声检测大鼠心功能,HE染色...目的探究盐诱导激酶2(SIK2)对大鼠心脏缺血再灌注损伤的影响及机制。方法建立大鼠心肌缺血再灌注损伤模型,随机分为假手术组、缺血再灌注组、SIK2抑制剂组,5只/组(造模前24 h左股静脉注射博舒替尼10 mg/kg)。超声检测大鼠心功能,HE染色观察大鼠心肌组织病理变化,透射电镜观察心肌细胞自噬情况,蛋白免疫印迹法检测各组大鼠心肌组织中SIK2和LC3B、Beclin-1、p62等自噬相关蛋白以及p-mTOR、mTOR、p-ULK1、ULK1相关通路蛋白含量。结果与假手术组比较,缺血再灌注组心肌组织病理损伤严重,自噬小体数量增加(P<0.05),同时SIK2蛋白表达增多(P<0.01);与缺血再灌注组相比,SIK2抑制剂组SIK2蛋白表达减少(P<0.01),心肌组织病理损伤较轻,自噬小体数量减少(P<0.05)。与假手术组相比,缺血再灌注组LVEF、FS值降低(79.33±3.40 vs 38.67±2.49,59.33±5.25 vs 19.33±1.25,P<0.001);与缺血再灌注组相比,SIK2抑制剂组LVEF、FS值升高(38.67±2.49 vs 59.33±3.40,19.33±1.25 vs 30.67±3.40,P<0.05),3组IVSDd、LVPWDd无明显差别(P>0.05)。与假手术组相比,缺血再灌注组LC3-Ⅱ/LC3-Ⅰ、Beclin-1蛋白表达增多,p62蛋白表达减少(P<0.01);与缺血再灌注组相比,SIK2抑制剂组LC3-Ⅱ/LC3-Ⅰ、Beclin-1蛋白表达减少,p62蛋白表达增多(P<0.05)。与假手术组相比,缺血再灌注组p-ULK1(Ser757)蛋白表达增多(P<0.01),p-mTOR蛋白表达减少(P<0.0001);与缺血再灌注组相比,SIK2抑制剂组p-ULK1(Ser757)蛋白表达减少(P<0.01),p-mTOR蛋白表达增多(P<0.05);各组mTOR、ULK1无明显差异(P>0.05)。结论SIK2可能通过mTOR/ULK1信号通路促进细胞自噬,对SIK2进行抑制,可以减少异常自噬,缓解心肌缺血再灌注损伤。展开更多
Salt-inducible kinase 2 (SIK2) is a member of the AMP-activated serine/threonine kinase family. It has been reported that inhibition of SIK2 can enhance the cytotoxicity of paclitaxel,1 promote premitotic apoptosis, a...Salt-inducible kinase 2 (SIK2) is a member of the AMP-activated serine/threonine kinase family. It has been reported that inhibition of SIK2 can enhance the cytotoxicity of paclitaxel,1 promote premitotic apoptosis, and lead to cell cycle arrest in the metaphase.2 Thus, targeting SIK2 may be a therapeutic strategy for cancers drug and radiotherapy resistance. Mitotic catastrophe is a type of abnormal mitosis leading to cell death characterized by the multipolar spindle and multinucleation, which was first discovered during an ionizing radiation (IR)-induced cell damage.3 However, the mechanism of mitotic catastrophe is not well understood. The present study aimed to assess the effect of the knockdown of SIK2 on IR-induced mitotic catastrophe.展开更多
基金supported by the National Natural Science Foundation of China to Jinhua Zhou(Nos.82172609)Jiangsu Social Development Project(Nos.BE2022729).
文摘Objectives:Our previous research demonstrated that SIC-19,an innovative inhibitor of salt-inducible kinase 2(SIK2),effectively reduces SIK2 protein levels through the ubiquitin-proteasome pathway and exhibits synthetic lethal effects with poly ADP-ribose polymerase(PARP)inhibitors in ovarian cancer.However,the role of SIC-19 in triplenegative breast cancer(TNBC)and pancreatic cancer(PC)remains poorly defined.This study aims to investigate whether SIC-19 combined with PARP inhibitors can induce synthetic lethal effects in TNBC and PC.Methods:Cell lines with high SIK2 expression were identified through Western blot analysis.The combination’s impact was evaluated using Cell Counting Kit-8(CCK8),clone formation,and apoptosis assays,as well as in vivo xenograft models.Results:Our findings indicated that the IC50 of SIC-19 was inversely correlated with endogenous SIK2 expression in TNBC and PC cell lines.SIC-19 modulates the homologous recombination repair pathway by suppressing levels of RAD50-pS635,thereby enhancing the sensitivity of TNBC and PC cells,as well as xenografts,to PARP inhibitors.Conclusion:These results underscore the potential of combining PARP inhibitors in combination with SIK2 inhibitors as a novel therapeutic approach to increase PARP inhibition’s effectiveness in treating TNBC and PC.This innovative combination therapy represents a promising approach for overcoming resistance mechanisms and improving the outcomes for patients with these challenging malignancies.
文摘目的探究盐诱导激酶2(SIK2)对大鼠心脏缺血再灌注损伤的影响及机制。方法建立大鼠心肌缺血再灌注损伤模型,随机分为假手术组、缺血再灌注组、SIK2抑制剂组,5只/组(造模前24 h左股静脉注射博舒替尼10 mg/kg)。超声检测大鼠心功能,HE染色观察大鼠心肌组织病理变化,透射电镜观察心肌细胞自噬情况,蛋白免疫印迹法检测各组大鼠心肌组织中SIK2和LC3B、Beclin-1、p62等自噬相关蛋白以及p-mTOR、mTOR、p-ULK1、ULK1相关通路蛋白含量。结果与假手术组比较,缺血再灌注组心肌组织病理损伤严重,自噬小体数量增加(P<0.05),同时SIK2蛋白表达增多(P<0.01);与缺血再灌注组相比,SIK2抑制剂组SIK2蛋白表达减少(P<0.01),心肌组织病理损伤较轻,自噬小体数量减少(P<0.05)。与假手术组相比,缺血再灌注组LVEF、FS值降低(79.33±3.40 vs 38.67±2.49,59.33±5.25 vs 19.33±1.25,P<0.001);与缺血再灌注组相比,SIK2抑制剂组LVEF、FS值升高(38.67±2.49 vs 59.33±3.40,19.33±1.25 vs 30.67±3.40,P<0.05),3组IVSDd、LVPWDd无明显差别(P>0.05)。与假手术组相比,缺血再灌注组LC3-Ⅱ/LC3-Ⅰ、Beclin-1蛋白表达增多,p62蛋白表达减少(P<0.01);与缺血再灌注组相比,SIK2抑制剂组LC3-Ⅱ/LC3-Ⅰ、Beclin-1蛋白表达减少,p62蛋白表达增多(P<0.05)。与假手术组相比,缺血再灌注组p-ULK1(Ser757)蛋白表达增多(P<0.01),p-mTOR蛋白表达减少(P<0.0001);与缺血再灌注组相比,SIK2抑制剂组p-ULK1(Ser757)蛋白表达减少(P<0.01),p-mTOR蛋白表达增多(P<0.05);各组mTOR、ULK1无明显差异(P>0.05)。结论SIK2可能通过mTOR/ULK1信号通路促进细胞自噬,对SIK2进行抑制,可以减少异常自噬,缓解心肌缺血再灌注损伤。
基金funded by grants from the National Natural Science Foundation of China(31470827,81773359,82073488,31870847 and 3127894).
文摘Salt-inducible kinase 2 (SIK2) is a member of the AMP-activated serine/threonine kinase family. It has been reported that inhibition of SIK2 can enhance the cytotoxicity of paclitaxel,1 promote premitotic apoptosis, and lead to cell cycle arrest in the metaphase.2 Thus, targeting SIK2 may be a therapeutic strategy for cancers drug and radiotherapy resistance. Mitotic catastrophe is a type of abnormal mitosis leading to cell death characterized by the multipolar spindle and multinucleation, which was first discovered during an ionizing radiation (IR)-induced cell damage.3 However, the mechanism of mitotic catastrophe is not well understood. The present study aimed to assess the effect of the knockdown of SIK2 on IR-induced mitotic catastrophe.
