Mitomycin C potentiates TRAIL-induced apoptosis through p53-independent upregulation of death receptors: evidence for the role of c-Jun N-terminal kinase activation.
The discovery of the molecular targets of chemotherapeutic medicines and their chemical footprints can validate and improve the use of such medicines. In the present report, we investigated the effect of mitomycin C (MMC), a classical chemotherapeutic agent on cancer cell apoptosis induced by TRAIL. We found that MMC not only potentiated TRAIL-induced apoptosis in HCT116 (p53-/-) colon cancer cells but also sensitized TRAIL-resistant colon cancer cells HT-29 to the cytokine both in vitro and in vivo. MMC also augmented the pro-apoptotic effects of two TRAIL receptor agonist antibodies, mapatumumab and lexatumumab. At a mechanistic level, MMC downregulated cell survival proteins, including Bcl2, Mcl-1 and Bcl-XL, and upregulated pro-apoptotic proteins including Bax, Bim and the cell surface expression of TRAIL death receptors DR4 and DR5. Gene silencing of DR5 by short hairpin RNA reduced the apoptosis induced by combination treatment of MMC and TRAIL. Induction of DR4 and DR5 was independent of p53, Bax and Bim but was dependent on c-Jun N terminal kinase (JNK) as JNK pharmacological inhibition and siRNA abolished the induction of the TRAIL receptors by MMC.
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute, Penn State Hershey Medical Center, Penn State College of Medicine, Hershey, PA, USA.
Hairong
H
Cheng
Bo
B
Hong
Lanlan
L
Zhou
Joshua E
JE
Allen
Guihua
G
Tai
Robin
R
Humphreys
David T
DT
Dicker
Yingqiu Y
YY
Liu
Wafik S
WS
El-Deiry
D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D053938:DNA Fragmentation; D017931:DNA Primers / Q000235:genetics; D004789:Enzyme Activation / Q000502:physiology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D005840:Gentian Violet; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D016685:Mitomycin / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy*; D011419:Propidium; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D017931:DNA Primers; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011419:Propidium; D016685:Mitomycin; C510234:lexatumumab; D048031:JNK Mitogen-Activated Protein Kinases; D005840:Gentian Violet; C507357:mapatumumab