PKCdelta protects human breast tumor MCF-7 cells against tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a number of tumorogenic or transformed cells, yet is relatively non-toxic to most normal cells, therefore, it is a promising agent for cancer therapy. However, some cancer cell lines were resistant to TRAIL cytoxicity, including MCF-7 breast cancer cells. The mechanism is not clear. Here, we report that protein kinase C delta (PKCdelta) protects MCF-7 cells from the recombinant soluble TRAIL (rsTRAIL)- mediated apoptosis. It was demonstrated that rottlerin, a PKCdelta inhibitor, sensitized MCF-7 cells to rsTRAIL cytoxicity. Combination of rottlerin and rsTRAIL inhibited PKCdelta translocation from the cytosol to membrane, and PKCdelta kinase activity on the cell membrane was kept pace with the change of PKCdelta expression. Moreover, inhibition of PKCdelta by interference RNA could facilitate apoptosis of MCF-7 cells induced by rsTRAIL. Further experiments on the signal machinery showed that rottlerin increased the sensitivity of MCF-7 cells to rsTRAIL by suppressing the transcription activity of NF-kappaB, and enhancing the caspase-processing to generate executive apoptotic signals. These findings indicate that PKCdelta functions as a survival factor protecting MCF-7 cells from the apoptosis induced by rsTRAIL.
Zhang
Jindan
J
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
Liu
Ning
N
Zhang
Jingchun
J
Liu
Shilian
S
Liu
Yanxin
Y
Zheng
Dexian
D
D000098:Acetophenones / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001578:Benzopyrans / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D000098:Acetophenones; D051017:Apoptosis Regulatory Proteins; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C085746:rottlerin; D051745:Protein Kinase C-delta; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases