Aspirin sensitizes cancer cells to TRAIL-induced apoptosis by reducing survivin levels.
OBJECTIVE
Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic antibodies targeting its receptors are promising cancer therapies because of their tumor selectivity, many tumors are resistant to TRAIL-based therapies. We examined whether the nonsteroidal anti-inflammatory drug aspirin sensitized cancer cells to TRAIL agonists in vitro and in vivo and investigated the underlying mechanism.


METHODS
The effects of aspirin on sensitivity to TRAIL agonists and expression of apoptosis regulators was determined in human breast cancer cell lines and xenograft tumors. The specific role of survivin depletion in the TRAIL-sensitizing effects of aspirin was determined by silencing survivin.


RESULTS
Aspirin sensitized human breast cancer cells, but not untransformed human mammary epithelial cells, to TRAIL-induced caspase activation and apoptosis by a cyclooxygenase-2-independent mechanism. Aspirin also sensitized breast cancer cells to apoptosis induced by a human agonistic TRAIL receptor-2 monoclonal antibody (lexatumumab). Aspirin treatment led to G1 cell cycle arrest and a robust reduction in the levels of the antiapoptotic protein survivin by inducing its proteasomal degradation, but did not affect the levels of many other apoptosis regulators. Silencing survivin with small interfering RNAs sensitized breast cancer cells to TRAIL-induced apoptosis, underscoring the functional role of survivin depletion in the TRAIL-sensitizing actions of aspirin. Moreover, aspirin acted synergistically with TRAIL to promote apoptosis and reduce tumor burden in an orthotopic breast cancer xenograft model.


CONCLUSIONS
Aspirin sensitizes transformed breast epithelial cells to TRAIL-based therapies in vitro and in vivo by a novel mechanism involving survivin depletion. These findings provide the first in vivo evidence for the therapeutic utility of this combination.
Lu
Meiling
M
Cell Death Regulation Laboratory, Department of Medicine and Cell and Molecular Biology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Strohecker
Anne
A
Chen
Feng
F
Kwan
Toni
T
Bosman
Joshua
J
Jordan
V Craig
VC
Cryns
Vincent L
VL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000187:drug effects*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000187:drug effects*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; C510234:lexatumumab; D001241:Aspirin; C507357:mapatumumab