The complex formed by two members of the S100 calcium-binding protein family, S100A8/A9, exerts apoptosisinducing activity in various cells of different origins. Here, we present evidence that the underlying molecular...The complex formed by two members of the S100 calcium-binding protein family, S100A8/A9, exerts apoptosisinducing activity in various cells of different origins. Here, we present evidence that the underlying molecular mechanisms involve both programmed cell death I （PCD I, apoptosis） and PCD II （autophagy）-like death. Treatment of cells with S100A8/A9 caused the increase of Beclin-1 expression as well as Atgl2-Atg5 formation. S100A8/A9-induced cell death was partially inhibited by the specific PI3-kinase class Ⅲ inhibitor, 3-methyladenine （3-MA）, and by the vacuole H＋-ATPase inhibitor, bafilomycin-A1 （Baf-A1）. S100A8/A9 provoked the translocation of BNIP3, a BH3 only pro-apoptotic Bcl2 family member, to mitochondria. Consistent with this finding, ATM-BNIP3 overexpression partially inhibited S100A8/A9-induced cell death, decreased reactive oxygen species （ROS） generation, and partially pro- tected against the decrease in mitochondrial transmembrane potential in S100A8/A9-treated ceils. In addition, either ATM-BNIP3 overexpression or N-acetyl-L-cysteine co-treatment decreased lysosomal activation in cells treated with S100A8/A9. Our data indicate that S100A8/A9-promoted cell death occurs through the cross-talk of mitochondria and lysosomes via ROS and the process involves BNIP3.展开更多
Triple-negative breast cancer is the tumor that lacks expressions of estrogen receptor（ER）, progesterone receptor（PR） and human epidermal growth factor receptor-2（HER2）. A regular chemotherapy cannot eradicate t...Triple-negative breast cancer is the tumor that lacks expressions of estrogen receptor（ER）, progesterone receptor（PR） and human epidermal growth factor receptor-2（HER2）. A regular chemotherapy cannot eradicate triple-negative breast cancer. In the present study, we aimed to develop a combined use of daunorubicin and rofecoxib to treat triple-negative breast cancer, and reveal the underlying mechanisms. A gradient elution HPLC-UV method was developed for quantification, and the evaluations were performed on the triple-negative breast cancer MDA-MB-231 cells using a high content screening system. The results demonstrated that daunorubicin alone was insensitive to the triple negative breast cancer cells, while the combined use of daunorubicin and rofecoxib was able to effectively kill these triple-negative cancer cells, exhibiting a rofecoxib concentration-dependent manner. The mechanism revealed that the augmented anticancer efficacy was associated with direct killing effect, inducing apoptosis and inducing autophagy by the combination treatment. Besides, the apoptosis signaling pathways were correlated to a cascade of reactions by activating apoptotic enzyme caspase family and by suppressing anti-apoptotic gene expressed protein Bcl-2 family. In conclusion, this study provided a fundamental evidence for further developing the combined use of daunorubicin and rofecoxib formulation, hence offering a promising strategy for eradicating the triple negative breast cancer.展开更多
文摘The complex formed by two members of the S100 calcium-binding protein family, S100A8/A9, exerts apoptosisinducing activity in various cells of different origins. Here, we present evidence that the underlying molecular mechanisms involve both programmed cell death I （PCD I, apoptosis） and PCD II （autophagy）-like death. Treatment of cells with S100A8/A9 caused the increase of Beclin-1 expression as well as Atgl2-Atg5 formation. S100A8/A9-induced cell death was partially inhibited by the specific PI3-kinase class Ⅲ inhibitor, 3-methyladenine （3-MA）, and by the vacuole H＋-ATPase inhibitor, bafilomycin-A1 （Baf-A1）. S100A8/A9 provoked the translocation of BNIP3, a BH3 only pro-apoptotic Bcl2 family member, to mitochondria. Consistent with this finding, ATM-BNIP3 overexpression partially inhibited S100A8/A9-induced cell death, decreased reactive oxygen species （ROS） generation, and partially pro- tected against the decrease in mitochondrial transmembrane potential in S100A8/A9-treated ceils. In addition, either ATM-BNIP3 overexpression or N-acetyl-L-cysteine co-treatment decreased lysosomal activation in cells treated with S100A8/A9. Our data indicate that S100A8/A9-promoted cell death occurs through the cross-talk of mitochondria and lysosomes via ROS and the process involves BNIP3.
基金National Natural Science Foundation of China(Grant No.81373343)the Key Grant of Beijing Natural Science Foundation(Grant No.7131009)
文摘Triple-negative breast cancer is the tumor that lacks expressions of estrogen receptor（ER）, progesterone receptor（PR） and human epidermal growth factor receptor-2（HER2）. A regular chemotherapy cannot eradicate triple-negative breast cancer. In the present study, we aimed to develop a combined use of daunorubicin and rofecoxib to treat triple-negative breast cancer, and reveal the underlying mechanisms. A gradient elution HPLC-UV method was developed for quantification, and the evaluations were performed on the triple-negative breast cancer MDA-MB-231 cells using a high content screening system. The results demonstrated that daunorubicin alone was insensitive to the triple negative breast cancer cells, while the combined use of daunorubicin and rofecoxib was able to effectively kill these triple-negative cancer cells, exhibiting a rofecoxib concentration-dependent manner. The mechanism revealed that the augmented anticancer efficacy was associated with direct killing effect, inducing apoptosis and inducing autophagy by the combination treatment. Besides, the apoptosis signaling pathways were correlated to a cascade of reactions by activating apoptotic enzyme caspase family and by suppressing anti-apoptotic gene expressed protein Bcl-2 family. In conclusion, this study provided a fundamental evidence for further developing the combined use of daunorubicin and rofecoxib formulation, hence offering a promising strategy for eradicating the triple negative breast cancer.
